Preventives/remedies for hot flash

ABSTRACT

It is intended to provide a preventing or treating agent for hot flash which comprises a nonpeptidic compound having gonadotropin releasing hormone antagonistic activity, in particular, a preventing or treating agent for hot flash which comprises a nonpeptidic compound having gonadotropin releasing hormone antagonistic activity, wherein said compound is capable of entering the brain.

TECHNICAL FIELD

The present invention relates to a preventing or treating agent forclimacteric disorder, in particular, hot flash.

BACKGROUND ART

Females accounting for a half of humans enter menopause due to loss ofthe ovarian function and then are suffered from various symptomsreferred to as climacteric disorder [vasomotor nervous disorder (hotflash, perspiration, palpitation, etc.), psychoneurotic disorder(excitement, insomnia, irritation, headache, etc.), atrophy ofurogenital system, lipid metabolic disorder, osteoporosis, etc.]including hot flash (a local rise in the body surface temperature, andvertigo and glow accompanying it). Although a main cause for climactericdisorder is thought to be decrease in the sex hormone levels, it is notclear. Climacteric disorder leads women to reduction in QOL (Quality ofLife) of their individual and social life. Thus, clarifying a cause ofclimacteric disorder and finding a treating method thereof are desired.In addition, sex hormone-dependent disease is treated by lowering thesex hormone level or inhibiting the sex hormone activity and suchtreatment produces climacteric disorder-like symptoms including hotflash. This is shown not only in women but also in men and this is aside effect of such treatment.

Although a cause of climacteric disorder is not clear, it is true thatdecrease in the sex hormone levels triggers it. Therefore, a sex hormonemay be supplemented as a treatment for climacteric disorder. Suchhormone replacement therapy shows a certain effect, but it has a problemof increase in carcinogenic risk. In addition, when treatment bylowering the sex hormone level or inhibiting the sex hormone activity isperformed, supplementation of a sex hormone weakens the original drugefficacy, being not preferable.

Lowering the sex hormone level decreases the negative feedback of thesex hormone and promotes synthesis and secretion of GnRH (gonadotropinreleasing hormone). Then, GnRH stimulates synthesis and secretion of LHand FSH to enhance their blood concentration. Therefore, variousclimacteric disorders including hot flash may be caused by increase inthe GnRH, LH or FSH level.

Synthesis and secretion of GnRH and expression of a receptor for GnRHwere confirmed not only in hypothalamus and pituitary gland but also inbrain, but the function has not yet been clarified well. From anexperiment of administration of GnRH or GnRH and an antagonist thereofinto the brain of a rat, it was suggested that increasing GnRH level wasinvolved in manifestation of hot flash and an antagonist of GnRH mightsuppress it. However, the antagonist used in the experiment was apeptidic antagonist (Brain Research 754 (1997) 88-94.) which wasdifficult to use clinically.

In addition, a method for suppressing hot flash accompanying prostatecancer treatment using PPI-149 which was a peptidic GnRH antagonist wasreported (JP-A 2002-512976 (WO99/55358)).

Regarding a preventing or treating agent for climacteric disorder, inparticular, hot flash, a medicament which is satisfactory to clinicaluse has not been reported yet. An object of the present invention is toprovide a preventing or treating agent for climacteric disorder, inparticular, hot flash. In the present invention, a preventing ortreating agent includes an improving agent.

DISCLOSURE OF INVENTION

The present inventors found out that non-peptidic compounds havinggonadotropin releasing hormone antagonistic activity suppress action ofintracerebral GnRH and thereby are effective as a preventing or treatingagent for hot flash, and as a result of further study based on thisfinding, completed the present invention.

That is, the present invention relates to:

[1] a preventing or treating agent for hot flash which comprises anon-peptidic compound having gonadotropin releasing hormone antagonisticactivity;

[2] the agent according to the above [1], wherein the compound is acompound capable of entering the brain,

[3] the agent according to the above [1], wherein the compound is afused heterocyclic compound,

[4] the agent according to the above [1], wherein the compound is acompound represented by the formula:

wherein R¹ represents (1) a hydrogen atom, (2) a group linking via acarbon atom, (3) a group linking via a nitrogen atom, (4) a grouplinking via an oxygen atom or (5) a group linking via a sulfur atom,

R² represents (1) a hydrogen atom, (2) a group linking via a carbonatom, (3) a group linking via a nitrogen atom, (4) a group linking viaan oxygen atom or (5) a group linking via a sulfur atom,

R³ represents (1) a hydrogen atom, (2) alkyl or (3) —(CH₂)_(p)Q (whereinp represents an integer of 0 to 3 and Q represents an optionallysubstituted homocyclic group or an optionally substituted heterocyclicgroup),

R⁴ represents (1) a hydrogen atom, (2) alkyl optionally substituted withalkoxy, (3) optionally substituted aryl, (4) optionally substitutedaralkyl or (5) optionally substituted cycloalkyl,

R⁵ represents (1) a hydrogen atom, (2) formyl, (3) cyano, (4) C₁₋₆alkyloptionally substituted with (i) a group linking via a sulfur atom or(ii) a group linking via an oxygen atom, (5) an optionally substitutedheterocyclic group, (6) a group linking via a nitrogen atom, (7) a grouplinking via an oxygen atom, (8) a group linking via a sulfur atom, (9)optionally esterified, thioesterified or amidated carboxyl or (10)—C(O)R⁷ (wherein R⁷ represents an optionally substituted hydrocarbongroup), and

R⁶ represents (1) a hydrogen atom or (2) a group linking via a carbonatom, or a salt or prodrug thereof;

[5] the agent according to the above [4], wherein R¹ is optionallysubstituted C₆₋₁₄ aryl, R² is (1) C₁₋₃alkyl substituted with a grouplinking via a nitrogen atom or (2) a group linking via a nitrogen atom,R³ is —(CH₂)_(p)Q (wherein p represents an integer of 0 to 3 and Qrepresents an optionally substituted homocyclic group or an optionallysubstituted heterocyclic group),

R⁴ is (1) C₁₋₆alkyl optionally substituted with C₁₋₆alkoxy or (2)optionally substituted C₆₋₁₄aryl;

[6] the agent according to the above [1], wherein the compound is acompound represented by the formula:

wherein R²¹ and R²² each represent (1) a hydrogen atom (2) hydroxy (3)C₁₋₄alkoxy, (4) C₁₋₄alkoxy-carbonyl or (5) optionally substitutedC₁₋₄alkyl, R²³ represents (1) a hydrogen atom, (2) halogen, (3) hydroxyor (4) optionally substituted C₁₋₄alkoxy, or two R²³ adjacent to eachother may be linked to form C₁₋₄ alkylenedioxy, R²⁴ represents (1) ahydrogen atom or (2) C₁₋₄alkyl, and R²⁶ represents (1) optionallysubstituted C₁₋₄alkyl or (2) a group represented by the formula:

wherein R²⁵ represents a hydrogen atom or may be taken together with R²⁴to form a heterocycle, and n represents an integer of 0 to 5, or a saltthereof;

[7] a method for preventing or treating hot flash, which comprisesadministering an effective amount of a non-peptidic compound havinggonadotropin releasing hormone antagonistic activity to a mammal;

[8] use of a non-peptidic compound having gonadotropin releasing hormoneantagonistic activity for preparation of a preventing or treating agentfor hot flash; and the like.

The “non-peptidic compound having gonadotropin releasing hormone (GnRH)antagonistic activity” (GnRH antagonist) may be any non-peptidiccompounds having gonadotropin releasing hormone antagonistic activity.

The non-peptidic compound having GnRH antagonistic activity may be, forexample, a compound having a molecular weight of 1,000 or less,preferably a compound having a molecular weight of 900 or less, morepreferably a compound having a molecular weight of 800 or less.

In addition, the compound preferably has good oral absorbability. Forexample, when 10 mg/kg of the compound is orally administered to amammal, the compound exhibits preferably an absorption rate of 10% orlarger, more preferably an absorption rate of 20% or larger.

In addition, the compound is preferably capable of entering the brain.

A particularly preferred example of the non-peptidic compound havingGnRH antagonistic activity is a fused heterocyclic compound meeting theaforementioned conditions.

Such a fused heterocyclic compound includes a compound represented bythe formula:

wherein R¹ represents (1) a hydrogen atom, (2) a group linking via acarbon atom, (3) a group linking via a nitrogen atom, (4) a grouplinking via an oxygen atom or (5) a group linking via a sulfur atom,

R² represents (1) a hydrogen atom, (2) a group linking via a carbonatom, (3) a group linking via a nitrogen atom, (4) a group linking viaan oxygen atom or (5) a group linking via a sulfur atom,

R³ represents (1) a hydrogen atom, (2) alkyl or (3) —(CH₂)_(p)Q (whereinp represents an integer of 0 to 3 and Q represents an optionallysubstituted homocyclic group or an optionally substituted heterocyclicgroup),

R⁴ represents (1) a hydrogen atom, (2) alkyl optionally substituted withalkoxy, (3) optionally substituted aryl, (4) optionally substitutedaralkyl or (5) optionally substituted cycloalkyl,

R⁵ represents (1) a hydrogen atom, (2) formyl, (3) cyano, (4) C₁₋₆alkyloptionally substituted with (i) a group linking via a sulfur atom or(ii) a group linking via an oxygen atom, (5) an optionally substitutedheterocyclic group, (6) a group linking via a nitrogen atom, (7) a grouplinking via an oxygen atom, (8) a group linking via a sulfur atom, (9)optionally esterified, thioesterified or amidated carboxyl or (10)—C(O)R⁷ (wherein R⁷ represents an optionally substituted hydrocarbongroup), and

R⁶ represents (1) a hydrogen atom or (2) a group linking via a carbonatom, (hereinafter, abbreviated as Compound (I) in some cases) or a saltor prodrug thereof.

A definition of each substituent in the Compound (I) is shown below.

The “group linking via a carbon atom” represented by R¹, R² or R⁶includes (1) optionally substituted alkyl, (2) optionally substitutedcycloalkyl, (3) optionally substituted alkenyl, (4) optionallysubstituted aryl, (5) optionally substituted aralkyl, (6) a heterocyclicgroup linking via a carbon atom (said heterocyclic group may besubstituted), (7) formyl, (8) optionally esterfied or amidated carboxyl,(9) cyano and (10) amidino.

The alkyl of the “optionally substituted alkyl” in the definition of the“group linking via a carbon atom” represented by R¹, R² or R⁶ includesstraight and branched C₁₋₆alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl, 3-methylpentyl, neohexyl and2,3-dimethylbutyl.

The substituent of the “optionally substituted alkyl” includes (1) C₆₋₁₄aryl (e.g. phenyl, naphthyl, etc.) optionally substituted with 1 to 4substituents selected from (i) hydroxyl, (ii) amino, (iii) mono- ordi-C₁₋₆ alkylamino (e.g. methylamino, ethylamino, propylamino,dimethylamino, diethylamino, etc.), (iv) C₁₋₆alkoxy (e.g. methoxy,ethoxy, propoxy, butoxy, pentoxy, hexyloxy, etc.) and (v) halogen (e.g.fluorine, chlorine, bromine, iodine), (2) hydroxyl, (3) carboxy, (4)nitro, (5) C₁₋₆ alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy,butoxy, pentoxy, hexyloxy, etc.), (6) C₁₋₆alkyl-carbonyloxy (e.g.acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,isovaleryloxy, pivaloyloxy, pentylcarbonyloxy, hexylcarbonyloxy, etc.),(7) C₁₋₆ alkylthio (e.g. methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio,pentylthio, hexylthio, etc.), (8) C₁₋₆alkylsulfinyl (e.g.methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl,butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl,pentylsulfinyl, hexylsulfinyl, etc.), (9) C₁₋₆alkylsulfonyl (e.g.methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,pentylsulfonyl, hexylsulfonyl, etc.), (10) halogen (e.g. fluorine,chlorine, bromine, iodine), (11) a group linking via a nitrogen atom and(12) a heterocyclic group.

The “group linking via a nitrogen atom” as the substituent of the“optionally substituted alkyl” includes (1) —NR⁸R⁹ (wherein R⁸represents a hydrogen atom, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ cycloalkyl, optionally substituted C₆₋₁₄aryl, optionally substituted C₇₋₂₀ aralkyl, acyl, optionally substitutedcarbamoyl or heterocyclic group, and R⁹ represents a hydrogen atom oroptionally substituted C₁₋₆alkyl), and (2) a heterocyclic group linkingvia a nitrogen atom (e.g. 1H-1-pyrrolyl, 1-imidazolyl, pyrazolyl,indolyl, 1H-1-indazolyl, 7-purinyl, 1-pyrrolidinyl, 1-pyrrolinyl,1-imidazolidinyl, pyrazolidinyl, piperazinyl, pyrazolinyl,1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl, 2-isoindolyl,2-(1,2,3,4-tetrahydro)isoquinolyl, etc.).

The C₁₋₆alkyl of the “optionally substituted C₁₋₆ alkyl” represented byR⁸ or R⁹ includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,3-methylpentyl, neohexyl, and 2,3-dimethylbutyl.

The substituent of the “optionally substituted C₁₋₆ alkyl” representedby R⁸ or R⁹ includes (1) C₁₋₆ alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl, 3-methylpentyl, neohexyl, 2,3-dimethylbutyletc.), (2) C₂₋₆ alkenyl (e.g. vinyl, 1-methylvinyl, 1-propenyl, allyletc.), (3) C₂₋₆ alkynyl (e.g. ethynyl, 1-propynyl, propargyl etc.), (4)C₃₋₆ cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyletc.), (5) C₅₋₇ cycloalkenyl (e.g. cyclopentenyl, cyclohexenyl etc.),(6) C₇₋₁₁ aralkyl (e.g. benzyl, a-methylbenzyl, phenethyl etc.), (7)C₆₋₁₄ aryl (e.g. phenyl, naphthyl etc.), (8) C₁₋₆ alkoxy (e.g. methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxyetc.), (9) C₆₋₁₄ aryloxy (e.g. phenoxy, 1-naphthoxy, 2-naphthoxy etc.),(10) C₁₋₆ alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryletc.), (11) C₆₋₁₄ aryl-carbonyl (e.g. benzoyl, 1-naphtylcarbonyl,2-naphtylcarbonyl etc.), (12) C₁₋₆ alkanoyloxy (e.g. formyloxy, acetoxy,propionyloxy, butyryloxy, isobutyryloxy, etc.), (13) C₆₋₁₄arylcarbonyloxy (e.g. benzoyloxy, 1-naphtylcarbonyloxy,2-naphtylcarbonyloxy etc.), (14) carboxy, (15) C₁₋₆alkoxycarbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl etc.), (16)carbamoyl, (17) N-mono-C₁₄ alkylcarbamoyl (e.g. N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-butylcarbamoyl etc.), (18) N,N-di-C₁₋₄ alkylcarbamoyl (e.g.N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl,N,N-dibutylcarbamoyl etc.), (19) cyclic aminocarbonyl (e.g.1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl,1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyletc.), (20) halogen (e.g. fluorine, chlorine, bromine, iodine), (21)C₁₋₄ alkyl substituted with 1 to 3 halogen (e.g. chloromethyl,dichloromethyl, trifluoromethyl, trifluoroethyl etc.), (22) oxo, (23)amidino, (24) imino, (25) amino, (26) mono- or di-C₁₋₄ alkylamino (e.g.methylamino, ethylamino, propylamino, isopropylamino, butylamino,isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino,dimethylamino, diethylamino, dipropylamino etc.), (27) 3- to 6-memberedcyclic amino optionally containing 1 to 3 heteroatoms selected from anoxygen atom, a sulfur atom and a nitrogen atom in addition to carbonatoms and a nitrogen atom (e.g. aziridinyl, azetidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidino,morpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl,N-ethylpiperazinyl etc.), (28) C₁₋₆ alkanoylamino (e.g. formylamino,acetylamino, trifluoroacetylamino, propionylamino, butyrylamino,isobutyrylamino etc.), (29) benzamide, (30) carbamoylamino, (31) (N-C₁₋₄alkylcarbamoyl)amino (e.g. (N-methylcarbamoyl)amino,(N-ethylcarbamoyl)amino, (N-propylcarbamoyl)amino,(N-isopropylcarbamoyl)amino, (N-butylcarbamoyl)amino etc.), (32)(N,N-di-C₁₋₄ alkylcarbamoyl)amino (e.g. (N,N-dimethylcarbamoyl)amino,(N,N-diethylcarbamoyl)amino, (N,N-dipropylcarbamoyl)amino,(N,N-dibutylcarbamoyl)amino etc.), (33) C₁₋₆ alkylenedioxy (e.g.—OCH₂O—, —O(CH₂)₂O—, —O(CH₂)₃O—, —O(CH₂)₄O—, —O(CH₂)₅O—, —O(CH₂)₆O—etc.), (34) dihydroboryl, (35) hydroxy, (36) epoxy, (37) nitro, (38)cyano, (39) mercapto, (40) sulfo, (41) sulfino, (42) phosphono, (43)sulfamoyl, (44) N-C₁₋₆ alkylsufamoyl (e.g. N-methylsulfamoyl,N-ethylsulfamoyl, N-propylsufamoyl, N-isopropylsulfamoyl,N-butylsufamoyl etc.), (45) N,N-diC₁₋₆ alkylsulfamoyl (e.g.N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl,N,N-dibutylsulfamoyl etc.), (46) C₁₋₆ alkylthio (e.g. methylthio,ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio,tert-butylthio etc.), (47) phenylthio, (48) C₁₋₆alkylsulfinyl (e.g.methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl etc.), (49)phenylsulfinyl, (50) C₁₋₆ alkylsulfonyl (e.g. methylsulfonyl,ethylsulfonyl, propylsulfonyl, butylsulfonyl etc.), and (51)phenylsulfonyl. The optionally substituted C₁₋₆ alkyl may have 1 to 6,preferably 1 to 3 substituents selected from the above-mentionedsubstituents at substitutable positions.

The C₃₋₆cycloalkyl of the “optionally substituted C₃₋₆ cycloalkyl”represented by R⁸ includes cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The substituent of the “optionally substituted C₃₋₆ cycloalkyl”represented by R⁸ includes the same substituents as those of the“optionally substituted C₁₋₆ alkyl” represented by R⁸ or R⁹ mentionedabove, and the optionally substituted C₃₋₆ cycloalkyl may have 1 to 6,preferably 1 to 3 substituents at substitutable positions.

The C₆₋₁₄ aryl of the “optionally substituted C₆₋₁₄ aryl” represented byR⁸ includes phenyl, naphthyl and anthracenyl.

The substituent of the “optionally substituted C₆₋₁₄ aryl” representedby R⁸ includes the same substituents as those of the “optionallysubstituted C₁₋₆ alkyl” represented by R⁸ or R⁹ mentioned aboveexcluding oxo and epoxy, and the optionally substituted C₆₋₁₄ aryl mayhave 1 to 6, preferably 1 to 3 substituents at substitutable positions.

The C₇₋₂₀ aralkyl of the “optionally substituted C₇₋₂₀ aralkyl”represented by R⁸ includes benzyl, phenethyl, phenylpropyl, benzhydryland trityl.

The substituent of the “optionally substituted C₇₋₂₀ aralkyl”represented by R⁸ includes the same substituents as those of the“optionally substituted C-₁₋₆ alkyl” represented by R⁸ or R⁹ mentionedabove, and the optionally substituted C₇₋₂₀ aralkyl may have 1 to 6,preferably 1 to 3 substituents at substitutable positions.

The “acyl” represented by R⁸ includes groups formed by linking the“optionally substituted C₁₋₆ alkyl”, the “optionally substituted C₃₋₆cycloalkyl”, the “optionally substituted C₆₋₁₄ aryl” or the “optionallysubstituted C₇₋₂₀ aralkyl” represented by R⁸ with carbonyl, sulfinyl orsulfonyl.

The substituent of the “optionally substituted carbamoyl” represented byR⁸ includes (1) optionally substituted C₁₋₆ alkyl, (2) optionallysubstituted C₃₋₆ cycloalkyl, (3) optionally substituted C₆₋₁₄ aryl, (4)optionally substituted C₇₋₂₀ aralkyl, (5) hydroxy, (6) optionallysubstituted C₁₋₆ alkoxy and (7) optionally substituted C₁₋₆alkoxy-carbonyl, and the optionally substituted carbamoyl may have 1 or2 substituents selected from these substituents.

Examples of the “optionally substituted C₁₋₆ alkyl” as the substituentof the “optionally substituted carbamoyl” represented by R⁸ are the sameas those of the “optionally substituted C₁₋₆ alkyl” represented by R⁸ orR⁹ mentioned above.

Examples of the “optionally substituted C₃₋₆ cycloalkyl”, the“optionally substituted C₆₋₁₄ aryl” and the “optionally substitutedC₇₋₂₀ aralkyl” as the substituent of the “optionally substitutedcarbamoyl” represented by R⁸ are the same as those of the “optionallysubstituted C₃₋₆ cycloalkyl”, the “optionally substituted C₆₋₁₄ aryl”and the “optionally substituted C₇₋₂₀ aralkyl” represented by R⁸mentioned above, respectively.

The C₁₋₆ alkoxy of the “optionally substituted C₁₋₆ alkoxy” as thesubstituent of the “optionally substituted carbamoyl” represented by R⁸includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentoxy, and hexyloxy.

The substituent of the “optionally substituted C₁₋₆ alkoxy” includes thesame substituents as those of the “optionally substituted C₁₋₆ alkyl”represented by R⁸ mentioned above, and the optionally substituted C₁₋₆alkoxy may have 1 to 6, preferably 1 to 3 substituents at substitutablepositions.

The “optionally substituted C₁₋₆ alkoxy-carbonyl” as the substituent ofthe “optionally substituted carbamoyl” represented by R⁸ includes groupsformed by linking the “optionally substituted C₁₋₆ alkoxy” as thesubstituent of the “optionally substituted carbamoyl” represented by R⁸mentioned above with carbonyl.

The “heterocyclic group” represented by R⁸ includes (1) a 5-memberedcyclic group containing 1 to 4 heteroatoms selected from an oxygen atom,a sulfur atom and a nitrogen atom in addition to carbon atoms (e.g.2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 6-isoxazolyl, 5-isoxazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-(1,2,4-oxadiazolyl),5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3-(1,2,4-thiadiazolyl),5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4-(1,2,3-thiadiazolyl),5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, oxoimidazinyl,dioxotriazinyl, pyrrolidinyl etc.), (2) a 6-membered cyclic groupcontaining 1 to 4 heteroatoms selected from an oxygen atom, a sulfuratom and a nitrogen atom in addition to carbon atoms (e.g. 2-pyridyl,3-pyridyl, 4-pyridyl, N-oxide-2-pyridyl, N-oxide-3-pyridyl,N-oxide-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,N-oxide-2-pyrimidinyl, N-oxide-4-pyrimidinyl, N-oxide-5-pyrimidinyl,2-thiomorpholinyl, 3-thiomorpholinyl, 2-morpholinyl, 3-morpholinyl,piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl,1,3-thiazinyl, 2-piperazinyl, 3-piperazinyl, triazinyl, oxotriazinyl,3-pyridazinyl, 4-pyridazinyl, pyrazinyl, N-oxide-3-pyridazinyl,N-oxide-4-pyridazinyl etc.), and (3) a bicyclic or tricyclic fusedcyclic group containing 1 to 4 heteroatoms selected from an oxygen atom,a sulfur atom and a nitrogen atom in addition to carbon atoms (e.g.benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo[1,5-b]pyridazinyl,triazolo[4,5-b]pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl,cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl,quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl,carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl,phenazinyl, phenothiazinyl, phenoxazinyl etc.).

Examples of the heterocyclic group as the substituent of the “optionallysubstituted alkyl” in the definition of the “group linking via a carbonatom” represented by R¹, R² or R⁶ are the same as those of the“heterocyclic group” represented by R⁸ mentioned above.

The cycloalkyl of the “optionally substituted cycloalkyl” in thedefinition of the “group linking via a carbon atom” represented by R¹,R² or R⁶ includes C₃₋₆ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The substituent of the “optionally substituted cycloalkyl” includes thesame substituents as those of the “optionally substituted alkyl” in thedefinition of the “group linking via a carbon atom” represented by R¹,R² or R⁶, and the optionally substituted cycloalkyl may have 1 to 6,preferably 1 to 3 substituents at substitutable positions.

The alkenyl of the “optionally substituted alkenyl” in the definition ofthe “group linking via a carbon atom” represented by R¹, R² or R⁶includes C₂₋₆ alkenyl such as vinyl, butadienyl and hexatrienyl.

The substituent of the “optionally substituted alkenyl” includes thesame substituents as those of the “optionally substituted alkyl” in thedefinition of the “group linking via a carbon atom” represented by R¹,R² or R⁶, and the optionally substituted alkenyl may have 1 to 6,preferably 1 to 3 substituents at substitutable positions.

The aryl of the “optionally substituted aryl” in the definition of the“group linking via a carbon atom” represented by R¹, R² or R⁶ includesC₆₋₁₄ aryl such as phenyl, naphthyl and anthracenyl.

The substituent of the “optionally substituted aryl” includes the samesubstituents as those of the “optionally substituted alkyl” in thedefinition of the “group linking via a carbon atom” represented by R¹,R² or R⁶, such as C₁₋₆ alkoxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbobnyl, sec-butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, hexyloxycarbonyl etc.), carbamoyl, and N-mono-C₁₋₆alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N-isopropylcarbamoyl etc.), N,N-di-C₁₋₆alkylcarbamoyl(e.g. N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyletc.), and the optionally substituted aryl may have 1 to 6, preferably 1to 3 substituents at substitutable positions.

The aralkyl of the “optionally substituted aralkyl” in the definition ofthe “group linking via a carbon atom” represented by R¹, R² or R⁶includes C₇₋₂₀ aralkyl such as benzyl, benzhydryl and trityl.

The substituent of the “optionally substituted aralkyl” includes thesame substituents as those of the “optionally substituted alkyl” in thedefinition of the “group linking via a carbon atom” represented by R¹,R² or R⁶, and the optionally substituted aralkyl may have 1 to 6,preferably 1 to 3 substituents at substitutable positions.

Examples of the “heterocyclic group linking via a carbon atom” in thedefinition of the “group linking via a carbon atom” represented by R¹,R² or R⁶ are the same as those of the heterocyclic group represented byR⁸.

The “heterocyclic group linking via a carbon atom” may be substitutedand the substituent includes the same substituents as those of the“optionally substituted alkyl” in the definition of the “group linkingvia a carbon atom” represented by R¹, R² or R⁶. The heterocyclic grouplinking via a carbon atom may have 1 to 6, preferably 1 to 3substituents at substitutable positions.

The “optionally esterified carboxyl” in the definition of the “grouplinking via a carbon atom” represented by R¹, R² or R⁶ includes a grouprepresented by —CO₂R¹⁰, wherein R¹⁰ represents hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl or a heterocyclic grouplinking via a carbon atom (said heterocyclic group may be substituted).

Examples of the “optionally substituted alkyl”, the “optionallysubstituted cycloalkyl”, the “optionally substituted aryl”, the“optionally substituted aralkyl” and the “heterocyclic group linking viaa carbon atom (said heterocyclic group may be substituted)” representedby R¹⁰ are the same as those of the “optionally substituted alkyl”, the“optionally substituted cycloalkyl”, the “optionally substituted aryl”,the “optionally substituted aralkyl” and the “heterocyclic group linkingvia a carbon atom (said heterocyclic group may be substituted)” as the“group linking via a carbon atom” represented by R¹, R² or R⁶,respectively.

The “optionally amidated carboxyl” in the definition of the “grouplinking via a carbon atom” represented by R¹, R² or R⁶ includes a grouprepresented by —CONR⁸R⁹, wherein R⁸ and R⁹ are as defined above.

Examples of the “group linking via a nitrogen atom” represented by R¹,R² or R⁵ are the same as those of the “group linking via a nitrogenatom” as the substituent of the “optionally substituted alkyl” in thedefinition of the “group linking via a carbon atom” represented by R¹,R² or R⁶.

The “group linking via an oxygen atom” represented by R¹, R² or R⁵includes a group represented by —OR¹¹, wherein R¹¹ represents optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted C₆₋₁₄ aryl, optionally substituted C₇₋₂₀ aralyklor an optionally substituted heterocyclic group.

Examples of the “optionally substituted C₁₋₆ alkyl” represented by R¹¹are the same as those of the “optionally substituted C₁₋₆alkyl”represented by R⁸ or R⁹ mentioned above.

Examples of the “optionally substituted C₃₋₆ cycloalkyl”, the“optionally substituted C₆₋₁₄ aryl”, the “optionally substituted C₇₋₂₀aralkyl” and the “optionally substituted heterocyclic group” representedby R¹¹ are the same as those of the “optionally substituted C₃₋₆cycloalkyl”, the “optionally substituted C₆₋₁₄ aryl”, the “optionallysubstituted C₇₋₂₀ aralkyl” and the “optionally substituted heterocyclicgroup” represented by R⁸ mentioned above.

The “group linking via a sulfur atom” represented by R¹, R² or R⁵includes a group represented by —SR¹¹, wherein R¹¹ is as defined above.

The alkyl represented by R³ includes C₁₋₆ alkyl such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl andhexyl.

The “optionally substituted homocyclic group” represented by Q includes(1) optionally substituted aryl and (2) optionally substitutedcycloalkyl.

The aryl of the “optionally substituted aryl” in the definition of the“optionally substituted homocyclic group” represented by Q includesC₆₋₁₄ aryl such as phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryland acenaphthylenyl.

The substituent of the “optionally substituted aryl” in the definitionof the “optionally substituted homocyclic group” represented by Qincludes (i) C₁₋₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), (ii) C₂₋₆alkenyl(e.g. vinyl, allyl, 1-butenyl, 2-butenyl etc.), (iii) C₂₋₆alkynyl (e.g.ethynyl, propargyl, 2-butynyl, 5-hexynyl etc.), (iv) C₃₋₆ cycloalkyl(e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), (v) C₆₋₁₄aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl etc.), (vi) C₇₋₁₄ aralkyl(e.g. benzyl, phenethyl etc.), (vii) nitro, (viii) hydroxyl, (ix)mercapto, (x) cyano, (xi) carbamoyl, (xii) carboxyl, (xiii) C₁₋₆alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl etc.), (xiv) sulfo, (xv) halogen (e.g. fluorine,chlorine, bromine, iodine), (xvi) C₁₋₆ alkoxy (e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, hexyloxy etc.) optionally substituted with C₁₋₆alkoxy (e.g.methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, hexyloxy etc.), (xvii) C₆₋₁₀ aryloxy (e.g.phenoxy, 1-naphthyloxy, 2-naphthyloxy etc.), (xviii) C₁₋₆alkylthio (e.g.methylthio, ethylthio, propylthio, isopropyothio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthioetc.), (xix) C₆₋₁₀ arylthio (e.g. phenylthio, 1-naphthylthio,2-naphthylthio etc.), (xx) C₁₋₆alkylsulfinyl (e.g. methylsulfinyl,ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl,isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl,hexylsulfinyl etc.), (xxi) C₆₋₁₀ arylsulfinyl (e.g. phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl etc), (xxii) C₁₋₆ alkylsulfonyl,(e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,pentylsulfonyl, hexylsulfonyl etc.), (xxiii) C₆₋₁₀ arylsulfonyl (e.g.phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), (xxiv)amino, (xxv) C₁₋₆ acylamino (e.g. formylamino, acetylamino,propionylamino, butyrylamino, isobutyrylamino, valerylamino etc.),(xxvi) mono-C₁₋₆ alkylamino (e.g. methylamino, ethylamino, propylamino,isopropylamino, butylamino etc.), (xxvii) di-C₁₋₆ alkylamino (e.g.dimethylamino, diethylamino, dipropylamino, diisopropylamino,dibutylamino etc.), (xxviii) C₃₋₆ cycloalkylamino (e.g.cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylaminoetc.), (xxix) C₆₋₁₀ arylamino (e.g. anilino, 1-naphthylamino,2-naphthylamino etc.), (xxx) C₁₋₆ acyl (e.g. formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl etc.), (xxxi) C₆₋₁₀ arylcarbonyl (e.g.benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl etc.), and (xxxii)C₁₋₄alkylenedioxy (e.g. —OCH₂O—, —(CH₂)₂O—, —O(CH₂)₃ O—, —O(CH₂)₄O—,(xxxiii) a 5- or 6-membered heterocyclic group containing 1 to 4heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogenatom in addition to carbon atoms (e.g. 2-thienyl, 3-thienyl, 2-furyl,3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl,5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 3-(1,2,4-oxadiazolyl), 5-(1,2,4-oxadiazolyl),1,3,4-oxadiazolyl, 3-(1,2,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl),1,3,4-thiadiazolyl, 4-(1,2,3-thiadiazolyl), 5-(1,2,3-thiadiazolyl),1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl,2H-tetrazolyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,2-thiomorpholinyl, 3-thiomorpholinyl, 2-morpholinyl, 3-morpholinyl,piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl,1,3-thiazinyl, 2-piperazinyl, 3-piperazinyl, triazinyl, oxotriazinyl,3-pyridazinyl, 4-pyridazinyl, pyrazinyl etc.), and the optionallysubstituted aryl may have 1 to 6, preferably 1 to 3 substituents atsubstitutable positions.

The cycloalkyl of the “optionally substituted cycloalkyl” in thedefinition of the “optionally substituted homocyclic group” representedby Q includes C₃₋₆ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The substituent of the “optionally substituted cycloalkyl” in thedefinition of the “optionally substituted homocyclic group” representedby Q includes oxo, thioxo, and the same substituents as those of the“optionally substituted aryl” in the definition of the “optionallysubstituted homocyclic group” represented by Q, and the optionallysubstituted cycloalkyl may have 1 to 6, preferably 1 to 3 substituentsat substitutable positions.

Examples of the heterocyclic group of the “optionally substitutedheterocyclic group” represented by Q are the same as those of the“heterocyclic group” represented by R⁸.

The substituent of the “optionally substituted heterocyclic group”represented by Q includes the same substituents as those of the“optionally substituted aryl” in the definition of the “optionallysubstituted homocyclic group” represented by Q, and the optionallysubstituted heterocyclic group may have 1 to 6, preferably 1 to 3substituents at substitutable positions.

The “alkyl” of the “alkyl optionally substituted with alkoxy”represented by R⁴ includes C₁₋₆ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl, 3-methylpentyl, neohexyl and2,3-dimethylbutyl.

The “alkoxy” in the “alkyl optionally substituted with alkoxy”represented by R⁴ includes C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy andhexyloxy.

The “aryl” of the “optionally substituted aryl” represented by R⁴includes C₆₋₁₄ aryl such as phenyl, 1-naphthyl and 2-naphthyl.

The substituent of the “optionally substituted aryl” represented by R⁴includes the same substituents as those of the “optionally substitutedaryl” in the definition of the “optionally substituted homocyclic group”represented by Q, and the optionally substituted aryl may have 1 to 6,preferably 1 to 3 substituents at substitutable positions.

The aralkyl of the “optionally substituted aralkyl” represented by R⁴includes C₇₋₂₀ aralkyl such as benzyl, benzhydryl and trityl.

The substituent of the “optionally substituted aralkyl” represented byR⁴ includes the same substituents as those of the “optionallysubstituted aryl” as an example of the “optionally substitutedhomocyclic group” represented by Q, and the optionally substitutedaralkyl may have 1 to 6, preferably 1 to 3 substituents at substitutablepositions.

The cycloalkyl of the “optionally substituted cycloalkyl” represented byR⁴ includes C₃₋₆ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl.

The substituent of the “optionally substituted cycloalkyl” representedby R⁴ includes the same substituents as those of the “optionallysubstituted aryl” in the definition of the “optionally substitutedhomocyclic group” represented by Q, and the optionally substitutedcycloalkyl may have 1 to 6, preferably 1 to 3 substituents atsubstitutable positions.

The “C₁₋₆ alkyl” of the “C₁₋₆ alkyl optionally substituted with (i) agroup linking via a sulfur atom or (ii) a group linking via an oxygenatom” represented by R⁵ includes C₁₋₆ alkyl such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, neohexyl and2,3-dimethylbutyl.

Examples of the “group linking via a sulfur atom” of the “C₁₋₆alkyloptionally substituted with (i) a group linking via a sulfur atom or(ii) a group linking via an oxygen atom” represented by R⁵ are the sameas those of the “group linking via a sulfur atom” represented by R¹ orR²

Examples of the “group linking via an oxygen atom” of the “C₁₋₆ alkyloptionally substituted with (i) a group linking via a sulfur atom or(ii) a group linking via an oxygen atom” represented by R⁵ are the sameas those of the “group linking via an oxygen atom” represented by R¹ orR².

Examples of the “optionally substituted heterocyclic group” representedby R⁵ are the same as those of the “optionally substituted heterocyclicgroup” represented by Q.

The “optionally esterified carboxyl” represented by R⁵ includes a grouprepresented by —CO₂R¹⁰, wherein R¹⁰ is as defined above.

The “optionally thioesterified carboxyl” represented by R⁵ includes agroup represented by —C(O)SR¹⁰, wherein R¹⁰ is as defined above.

The “optionally amidated carboxyl” represented by R⁵ includes a grouprepresented by —CONR⁸R⁹, wherein R⁸ and R⁹ are as defined above.

The “optionally substituted hydrocarbon group” represented by R⁷includes (1) optionally substituted alkyl, (2) optionally substitutedcycloalkyl, (3) optionally substituted alkenyl, (4) optionallysubstituted aryl, and (5) optionally substituted aralkyl.

Examples of the “optionally substituted alkyl”, the “optionallysubstituted cycloalkyl”, the “optionally substituted alkenyl”, the“optionally substituted aryl” and the “optionally substituted aralkyl”as the “optionally substituted hydrocarbon group” represented by R⁷ arethe same as those of the “optionally substituted alkyl”, the “optionallysubstituted cycloalkyl”, the “optionally substituted alkenyl”, the“optionally substituted aryl” and the “optionally substituted aralkyl”as the “optionally substituted hydrocarbon group” represented by R¹, R²or R⁶, resprectively.

R¹ is preferably optionally substituted C₆₋₁₄ aryl.

R is preferably (1) C₁₋₆ alkyl (particularly C₁₋₃ alkyl) substitutedwith a group linking via a nitrogen atom or (2) a group linking via anitrogen atom.

R³ is preferably a group represented by —(CH₂)_(p)Q, wherein prepresents an integer of 0 to 3 and Q represents an optionallysubstituted homocyclic group or an optionally substituted heterocyclicgroup.

R⁴ is preferably (1) C₁₋₆ alkyl optionally substituted with C₁₋₆ alkoxyor (2) optionally substituted C₆₋₁₄ aryl.

R⁵ is preferably —C(O)R⁷, wherein R⁷ represents an optionallysubstituted hydrocarbon group.

R⁶ is preferably a hydrogen atom.

is preferably

Compound (I) is preferably a compound represented by the formula:

wherein respective symbols are as defined above (hereinafter,abbreviated as Compound (Ia)). Inter alia, preferred is Compound (Ia)wherein R¹ is optionally substituted C₆₋₁₄ aryl, R² is (1) C₁₋₃ alkylsubstituted with a group linking via a nitrogen atom or (2) a grouplinking via a nitrogen atom, R³ is a group represented by —(CH₂)_(p)Q(wherein p represents an integer of 0 to 3, and Q represents anoptionally substituted homocyclic group or an optionally substitutedheterocyclic group), and R⁴ is (1) C₁₋₆ alkyl optionally substitutedwith C₁₋₆ alkoxy or (2) optionally substituted C₆₋₁₄ aryl.

Inter alia, preferred is Compound (I) represented by the formula:

wherein R²¹ and R²² each represent (1) a hydrogen atom, (2) hydroxy, (3)C₁₋₄ alkoxy, (4) C₁₋₄ alkoxy-carbonyl or (5) optionally substituted C₁₋₄alkyl,

R²³ represents (1) a hydrogen atom, (2) halogen, (3) hydroxy or (4)optionally substituted C₁₋₄ alkoxy, or two R²³ adjacent to each othermay be taken together to form C₁₋₄ alkylenedioxy,

R²⁴ represents (1) a hydrogen atom or (2) C₁₋₄ alkyl

R²⁶ represents (1) optionally substituted C₁₋₄ alkyl or (2) a grouprepresented by the formula:

(wherein R²⁵ represents a hydrogen atom, or may be linked with R²⁴ toform a heterocycle), and

n represents an integer of 0 to 5 (hereinafter, abbreviated as Compound(Ib)).

The “C₁₋₄ alkoxy” represented by R²¹ or R²² includes methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.Among them, C₁₋₃ alkoxy is preferable, and methoxy is furtherpreferable.

The “C₁₋₄ alkoxy-carbonyl” represented by R²¹ or R²² includesmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl andtert-butoxycarbonyl. Among them, C₁₋₃ alkoxy-carbonyl is preferable, andmethoxycarbonyl is further preferable.

The “C₁₋₄ alkyl” of the “optionally substituted C₁₋₄ alkyl” representedby R²¹ or R²² includes straight C₁₋₄ alkyl (e.g. methyl, ethyl, propyl,butyl etc.) and branched C₃₋₄ alkyl (e.g. isopropyl, isobutyl,sec-butyl, tert-butyl etc.). Among them, C₁₋₃ alkyl is preferable and,inter alia, ethyl is preferable.

The “substituent” of the “optionally substituted C₁₋₄ alkyl” representedby R²¹ or R²² includes (i) hydroxy, (ii) C₁₋₇ acyloxy (e.g. C₁₋₆alkyl-carbonyloxy such as acetoxy and propionyloxy), (iii) benzoyloxy,(iv) amino optionally substituted with 1 or 2 substituents selected fromC₁₋₆ alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl etc.), benzyloxycarbonyl, C₁₋₄ acyl (e.g. C₁₋₃alkyl-carbonyl such as acetyl and propionyl), C₁₋₄ alkyl (e.g. methyl,ethyl, propyl, butyl etc.) and C₁₋₃ alkylsulfonyl (e.g. methansulfonyletc.) (e.g. amino, dimethylamino, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino,acetylamino, methanesufulonylamino etc.), (v) C₁₋₁₀ alkoxy (e.g.methoxy, ethoxy, propoxy, tert-butoxy etc.), (vi) C₃₋₇cycloalkyloxycarbonyloxy-C₁₋₃ alkoxy (e.g.cyclohexyloxycarbonyloxy-1-ethoxy etc.) and (vii) C₁₋₃ alkoxy-C₁₋₃alkoxy (e.g. methoxymethoxy, methoxyethoxy etc.). Among them, hydroxylis preferable.

The “C₁₋₄ alkyl” of the “optionally substituted C₁₋₄ alkyl” representedby R²¹ or R²² may have 1 to 5, preferably 1 to 3 of the aforementionedsubstituents at substitutable positions. When the number of substituentsis 2 or more, respective substituents may be the same or different.

One of R²¹ and R²² is preferably a hydrogen atom and the other ispreferably C₁₋₃ alkoxy.

The “halogen” represented by R²³ includes fluorine, chlorine, bromineand iodine. Among them, chlorine is preferable.

The “C₁₋₄ alkoxy” of the “optionally substituted C₁₋₄ alkoxy”represented by R²³ includes methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy and tert-butoxy. Among them, methoxy ispreferable.

The “substituent” of the “optionally substituted C₁₋₄ alkoxy”represented by R²³ includes the same groups as those of the “optionallysubstituted C₁₋₄ alkyl” represented by R²¹ or R²². Among them,C₁₋₄alkoxy is preferable.

The C₁₋₄ alkoxy may have 1 to 5, preferably 1 to 3 of the aforementionedsubstituents at substitutable positions. When the number of substituentsis 2 or more, respective substituents may be the same or different.

The “C₁₋₄ alkylenedioxy” formed by linking two R²³ adjacent to eachother includes methylenedioxy and ethylenedioxy.

R²³ is preferably a hydrogen atom.

The “C₁₋₄ alkyl” represented by R²⁴ includes straight C₁₋₄ alkyl (e.g.methyl, ethyl, propyl, butyl, etc.) and branched C₃₋₄ alkyl (e.g.isopropyl, isobutyl, sec-butyl, tert-butyl etc.). Among them, C₁₋₃ alkylis preferable. Inter alia, methyl is preferable.

Examples of the “optionally substituted C₁₋₄ alkyl” represented by R²⁶are the same as those of the “optionally substituted C₁₋₄ alkyl”represented by R²¹ or R²².

The “heterocycle” formed by linking R²⁴ and R²⁵ includes a 5- or6-membered nitrogen-containing heterocyclic group. When R²⁴ and R²⁵ arelinked, a group represented by the formula:

includes a group represented by the formula:

Among them, a group represented by the formula:

is preferable.

R²⁶ is preferably a group represented by the formula:

wherein R²⁵ is as defined above.

R²⁴ is preferably C₁₋₃alkyl, and R²⁵ is preferably a hydrogen atom.

Preferably, n is an integer of 0 to 2.

Preferred Compound (I) includes a compound represented by the formula:

wherein respective symbols are as defined above (hereinafter,abbreviated as Compound (Ic)).

More preferred is Compound (Ic) wherein R²¹ is hydroxy, methoxy or C₁₋₃alkyl; R²² is a hydrogen atom or C₁₋₃ alkyl; R²⁴ is C₁₋₃ alkyl; R²⁵ is ahydrogen atom; and n is 0.

Inter alia, preferred is Compound (Ic) wherein R²¹ is methoxy; R²² andR²⁵ each are a hydrogen atom; R²⁴ is C₁₋₃ alkyl; R²⁵ is a hydrogen atom;and n is 0.

In addition, preferred Compound (I) includes Compound (Ib) wherein R²¹is (i) hydroxy, (ii) C₁₋₄ alkoxy or (iii) C₁₋₄ alkyl optionallysubstituted with hydroxy or C₁₋₄ alkyl-carbonyloxy; R²² is a hydrogenatom, C₁₋₄ alkyl or C₁₋₄ alkoxy-carbonyl; R²³ is a hydrogen atom,halogen, hydroxy or C₁₋₄ alkoxy-C₁₋₄ alkoxy, or two R²³ adjacent to eachother are taken together to form C₁₋₃ alkylenedioxy; R²⁴ is a hydrogenatom or C₁₋₃ alkyl; R²⁶ is C₁₋₄ alkoxy-C₁₋₄ alkyl or a group representedby the formula:

(wherein R²⁵ represents a hydrogen atom, or R²⁴ and R²⁵ are linked toform a 5- or 6-membered heterocycle); and n is 1 or 2.

Embodiment of Compound (I) includes5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-hydroxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methylureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-ethylureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneand their salts.

Inter alia,5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dioneor a salt thereof is preferable.

A salt of Compound (I) is preferably a physiologically acceptable acidaddition salt. Such a salt includes salts with inorganic acids (e.g.hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid etc.), and salts with organic acids (e.g. formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidetc.). When Compound (I) has an acidic group, it may form aphysiologically acceptable salt with an inorganic base (e.g. alkalimetal salt such as sodium, potassium, calcium and magnesium or alkalineearth metal, ammonia etc.) or an organic base (e.g. trimethylamine,triethylemine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine etc.).

Compound (I) can be prepared by a known method such as the methoddescribed in WO95/28405, JP-A 9-169766, WO96/24597, WO97/14697,WO97/41126, WO00/00493 or WO00/56739, or the similar method.

A prodrug of Compound (I) refers to a compound which is converted intoCompound (I) by a reaction with an enzyme or gastric acid in vivo.

A prodrug of Compound (I) includes, when Compound (I) has amino, acompound in which the amino is acylated, alkylated or phosphorylated(e.g. a compound obtained by eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation ortert-butylation of the amino of Compound (I)); when Compound (I) hashydroxy, a compound in which the hydroxy is acylated, alkylated,phosphorylated or borated (e.g. a compound obtained by acetylation,palmitoylation, propanoylation, pivaloylation, succinylation,fumarylation, alanylation or dimethylaminomethylcarbonylation of thehydroxy of Compond (I)); and when Compound (I) has carboxyl, a compoundin which the carboxyl is esterified or amidated (e.g. a compoundobtained by ethylesterification, phenylesterification,carboxymethylesterification, dimethylaminomethylesterification,pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification,phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification or methylamidation of thecarboxyl of Compound (I)). These compounds can be prepared by a methodknown per se.

Alternatively, a prodrug of Compound (I) may be a compound which isconverted into Compound (I) under the physiological condition asdescribed in “Iyakuhin No Kaihatsu (Development of Drugs)”, Vol. 7,Molecular Designing, published by Hirokawa Shoten, 1990, pages 163-198.

A prodrug of Compound (I) may be itself or in the form ofpharmacologically acceptable salt. Such salt includes, when a prodrug ofCompound (I) has an acidic group such as carboxyl, salts with inorganicbases (e.g. alkali metal such as sodium and potassium, alkaline earthmetal such as calcium and magnesium, transition metal such as zinc, ironand copper) and salts with organic bases (e.g. organic amines such astrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine andN,N′-dibenzylethylenediamine, and basic amino acids such as arginine,lysine and ornithine).

When a prodrug of Compound (I) has a basic group such as amino, the saltof the prodrug includes salts with inorganic acids or organic acids(e.g. hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,carbonic acid, bicarbonic acid, formic acid, acetic acid, propionicacid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid,maleic acid, citric acid, succinic acid, malic acid, methanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid etc.), and salts withacidic amino acids such as aspartic acid and glutamic acid.

In addition, a prodrug of Compound (I) may be hydrous or anhydrous.

Compound (I) may have one or more asymmetric carbons and, regardingthese asymmetric carbons, both of R configuration and S configurationare included in the present invention.

Compound (I) may be labeled with an isotope element (e. g. ³H, ¹⁴C ³⁵S)In addition, the non-peptidic compound having gonadotropin releasinghormone antagonistic activity includes a compound represented by theformula:

wherein one of W and Y is a nitrogen atom and the other is a carbonatom, or both of them are nitrogen atoms, X is a nitrogen atom or acarbon atom, m is an integer of 0 to 3, R³¹, R³² and R³³ are the same ordifferent and each is (i) a hydrogen atom or (ii) a group linking via acarbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, R³⁴ is agroup linking via a carbon atom, R³⁵ is a hydrogen atom, halogen (e.g.fluorine, chlorine, bromine, iodine) or a group linking via a carbonatom or an oxygen atom, R³⁶ is a hydrogen atom or a group linking via acarbon atom, and R³⁷ is an optionally substituted homocyclic or anoptionally substituted heterocyclic group, and the broken linerepresents a single bond or a double bond (hereinafter, abbreviated asCompound (II) in some cases), or a salt thereof.

Respective substituents in Compound (II) are described in detail below.In the Compound (II), the group linking via a carbon atom includes (1)an optionally substituted hydrocarbon group, (2) an optionallysubstituted acyl group, (3) an optionally substituted heterocyclic grouplinking via a carbon atom, (4) an optionally esterified or amidatedcarboxyl group and (5) a cyano group.

In the aforementioned formula, the group linking via a nitrogen atomincludes (1) a nitro group and (2) a group represented by the formula—NR³⁸R³⁹, wherein R³⁸ represents hydrogen, an optionally substitutedhydrocarbon group, an optionally substituted acyl group, optionallysubstituted hydroxyl, an optionally substituted heterocyclic group or agroup represented by —S(O)_(t)—R⁴² (wherein t represents an integer of 0to 2, and R⁴² represents a hydrogen atom or an optionally substitutedC₁₋₁₀ hydrocarbon group), R³⁹ represents hydrogen, an optionallysubstituted hydrocarbon group or an optionally substituted acyl group,or R³⁸ and R³⁹ may be taken together with the adjacent atom to form anoptionally substituted cyclic amino group.

In the aforementioned formula, the group linking via an oxygen atomincludes optionally substituted hydroxy. The optionally substitutedhydroxy is represented by the formula —OR⁴³ wherein R⁴³ represents ahydrogen atom, or an optionally substituted C₁₋₁₀ hydrocarbon, C₁₋₂₀acyl, C₁₋₂₀ alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl,heptylsulfonyl, octylsulfonyl, nonylsulfonyl, decylsulfonyl,undecylsulfonyl, dodecylsulfonyl, tridecylsulfonyl, tetradecylsulfonyl,pentadecylsulfonyl etc.), C₆₋₁₄ arylsulfonyl (e.g. phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsulfonyl etc.) or heterocyclic group.

In the aforementioned formula, the group linking via a sulfur atomincludes a group represented by the formula —S(O)_(t)R⁴⁴ wherein trepresents an integer of 0 to 2, and R⁴⁴ represents a hydrogen atom, oran optionally substituted hydrocarbon or heterocyclic group.

The optionally esterified carboxyl group includes a group represented bya formula —COOR⁵¹ wherein R⁵¹ represents a hydrogen atom or anoptionally substituted C₁₋₁₀ hydrocarbon group.

The optionally amidated carboxyl group includes a group represented bythe formula —CONR⁴⁵R⁴⁶ wherein R⁴⁵ represents a hydrogen atom, anoptionally substituted hydrocarbon group or an alkoxy group (e.g. C₁₋₆alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy) and R⁴⁶ represents ahydrogen atom or an optionally substituted hydrocarbon group, or R⁴⁵ andR⁴⁶ may be taken together with the adjacent nitrogen atom to form anoptionally substituted cyclic amino group. The optionally amidatedcarboxyl group includes a group represented by —CONH₂, and a mono- ordi-C₁₋₁₅ alkylcarbamoyl group, preferably a mono- or di-C₁₋₁₀alkylcarbamoyl group (e.g. methylcarbamoyl, ethylcarbamoyl,propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,sec-butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl,hexylcarbamoyl, dimethylcarbamoyl, methylethylcarbamoyl etc.).

The hydrocarbon group of the aforementioned optionally substitutedhydrocarbon group is preferably a C₁₋₂₀ hydrocarbon group (preferablyC₁₋₁₀ hydrocarbon group). The C₁₋₂₀ hydrocarbon group includes (1) C₁₋₁₅alkyl (e.g methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, tridecyl, tetradecyl, pentadecyl, etc.; inter alia, preferablyC₁₋₁₀ alkyl, more preferably C₁₋₆ alkyl), (2) C₃₋₁₀ cycloalkyl (e.g.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexl, cycloheptyl,cyclooctyl, cyclononyl, etc.; inter alia, preferably a C₃₋₆ cycloalkyl),(3) C₂₋₁₀ alkenyl (e.g. vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl,3-butenyl, butadienyl, 2-methylallyl, hexatrienyl, 3-octenyl, etc.;inter alia, preferably C₂₋₆ alkenyl), (4) C₂₋₁₀ alkynyl (e.g. ethynyl,2-propynyl, butynyl, 3-hexynyl, etc.; inter alia, preferably C₂₋₆alkynyl), (5) C₃₋₁₀ cycloalkenyl (e.g. cyclopropenyl, cyclopentenyl,cyclohexenyl, etc.; inter alia, preferably C₃₋₆ cycloalkenyl), (6) C₆₋₁₄aryl (e.g. phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, etc.;inter alia, preferably phenyl or naphthyl), and (7) C₇₋₂₀ aralkyl (e.g.C₆₋₁₄ aryl-C₁₋₆ alkyl such as benzyl, phenethyl and benzhydryl; interalia, preferably phenyl-C₁₋₆ alkyl such as benzyl and phenethyl).

The hydrocarbon group may have 1 to 6, preferably 1 to 5, furtherpreferably 1 to 3 substituents at substitutable positions. Thesubstituent includes (1) halogen (e.g. fluorine, chlorine, bromine,iodine), (2) nitro, (3) nitroso, (4) cyano, (5) hydroxy optionallysubstituted with, for example, (i) C₁₋₆ alkyl [the C₁₋₆ alkyl may besubstituted with 1 to 3 substituents selected from hydroxyl, C₁₋₆alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkoxy, C₁₋₃ alkylthio, hydroxyl-C₁₋₃ alkoxy,C₁₋₆ alkyl-carbonyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbamoyl, a 5- to8-membered heterocyclic group (same as “5- or 8-membered heterocyclicgroup containing 1 to 4 heteroatoms selected from an oxygen atom, asulfur atom and a nitrogen atom in addition to carbon atoms” describedbelow) and halogen (e.g. fluorine, chlorine, bromine, iodine)], (ii)C₁₋₄ acyl (e.g. C₁₋₄alkanoyl (formyl, acetyl, propionyl, butyryl,isobutyryl etc.), C₃₋₄alkenoyl (vinylcarbonyl, 1-propenylcarbonyl,2-propenylcarbonyl etc.), (iii) C₇₋₂₀aralkyl (the C₇₋₂₀aralkyl is C₆₋₁₄aryl-C₁₋₆ alkyl and may be substituted with 1 to 3, preferably 1 halogen(e.g. fluorine, chlorine, bromine, iodine), C₁₋₃ alkoxy or C₁₋₄alkyl,(iv) C₆₋₁₄aryl (the C₆₋₁₄aryl may be substituted with 1 to 3, preferably1 halogen (e.g. fluorine, chlorine, bromine, iodine), (v) C₂₋₆alkenyl,(vi) C₃₋₇cycloalkyl, (vii) C₁₋₃alkoxy-carbonyl, (viii) mono- ordi-C₁₋₆alkylamino, (ix) C₂₋₆alkenylamino, (x) C₁₋₆alkyl-carbonyl or (xi)C₃₋₆cycloalkyloxy-carbonyl, (6) a group represented by the formula—S(O)_(t)R⁴⁷, wherein t represents an integer of 0 to 2, and R⁴⁷represents a hydrogen atom or a hydrocarbon group optionally substitutedwith 1 to 3, preferably 1 substituent [e.g. halogen (e.g. fluorine,chlorine, bromine, iodine), nitro, cyano, hydroxy, oxo, thioxo, carboxy,cyano-C₆₋₁₄aryl, halogenoC₆₋₁₄aryl etc.] at a substitutable position,wherein the hydrocarbon group includes a C₁₋₂₀ hydrocarbon group,preferably, C₁₋₆alkyl, C₆₋₁₄aryl or C₇₋₂₀aralkyl, (7) an optionallysubstituted amino group [e.g. a group represented by the formula—NR⁴⁸R⁴⁹ wherein R⁴⁸ and R⁴⁹ are the same or different and representC₁₋₆alkyl, C₁₋₆alkylamino-C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl,C₃₋₇cycloalkyl, phenyl, phenyl-C₁₋₆alkyl, C₁₋₆alkanoyl, C₃₋₆ alkenoyl,C₃₋₇cycloalkyl-carbonyl, phenyl-C₁₋₆alkyl-carbonyl, C₁₋₆alkoxy-carbonyl,phenyl-C₁₋₆alkoxy-carbonyl or a 5- to 8-membered heterocyclic group(same as “5- to 8-membered heterocyclic group containing 1 to 4heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogenatom in addition to carbon atoms” described below)], (8) a grouprepresented by the formula —COR⁵⁰ wherein R⁵⁰ represents (i) a hydrogenatom, (ii) hydroxy, (iii) C₁₋₁₀alkyl, (iv) C₁₋₆ alkoxy (this alkoxy maybe substituted with C₆₋₁₄ aryl optionally substituted with 1 to 3,preferably 1 substituent such as halogen or nitro at a substitutableposition) (v) C₃₋₆cycloalkyl, (vi) C₆₋₁₄aryl, (vii) C₆₋₁₄ aryloxy,(viii) C₇₋₂₀aralkyl, or (ix) an optionally substituted amino grouprepresented by the formula —NR⁴⁰R⁴¹ wherein R⁴⁰ represents hydrogen, anoptionally substituted C₁₋₁₀hydrocarbon, C₁₋₂₀acyl, hydroxy orheterocyclic group, or a group represented by the formula —S(O)_(t)—R⁴²(wherein t represents an integer of 0 to 2, and R⁴² represents ahydrogen atom, an optionally substituted C₁₋₁₀hydrocarbon group, or aheterocyclic group), R⁴¹ represents hydrogen or a C₁₋₁₀hydrocarbongroup, or R⁴⁰ and R⁴¹ may be taken together with the adjacent nitrogenatom to form an optionally substituted cyclic amino group), or (x) a 5-to 8-membered heterocyclic group (same as “5- to 8-membered heterocyclicgroup containing 1 to 4 heteroatoms selected from an oxygen atom, asulfur atom and a nitrogen atom in addition to carbon atoms” describedbelow) (e.g. preferably C₁₋₆ alkanoyl, C₃₋₆alkenoyl,C₁₋₆alkoxy-carbonyl, etc.) , (9) a 5- to 8-membered heterocyclic groupcontaining 1 to 4 heteroatoms selected from a nitrogen atom, an oxygenatom and a sulfur atom, (10) sulfo, (11) C₆₋₁₄aryl, (12) C₃₋₁₀cycloalkyl, (13) C₁₋₆alkylenedioxy (e.g. methylenedioxy, ethylenedioxy,propylenedioxy, 2,2-dimethylenedioxy etc.), (14) oxo, (15) thioxo, (16)C₂₋₄alkynyl, (17) C₂₋₁₀alkenyl (preferably C₂₋₆alkenyl), (18)C₇₋₂₀aralkyl (e.g. C₆₋₁₄ aryl-C₁₋₆alkyl), (19) amidino and (20) azido.

Respective groups used in the explanation of a “substituent” which theaforementioned “hydrocarbon group” may have are exemplified below.

The C₁₋₁₀alkyl includes methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl (i.e. C₁₋₄ alkyl), pentyl, hexyl (i.e.C₁₋₆alkyl), heptyl, octyl, nonyl, and decyl.

The C₃₋₁₀cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl (i.e. C₃₋₆cycloalkyl), cycloheptyl (i.e. C₃₋₇cycloalkyl),cyclooctyl, cyclononyl, and cyclodecyl.

The C₂₋₁₀alkenyl includes vinyl, allyl, isopropenyl, 1-butenyl,2-butenyl, 3-butenyl, butadienyl, 2-methylallyl, hexatrienyl (i.e.C₂₋₆alkenyl), and 3-octenyl.

The C₂₋₄alkynyl includes ethynyl, 2-propynyl, and butynyl.

The C₁₋₆alkoxy includes methoxy, ethoxy, propoxy, isopropoxy (i.e.C₁₋₃alkoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The C₁₋₃alkoxy-C₁₋₃alkoxy includes methoxymethoxy, methoxyethoxy,methoxypropoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy,propoxymethoxy, propoxyethoxy, and propoxypropoxy.

The C₁₋₃alkylthio includes methylthio, ethylthio, propylthio, andisopropylthio.

The hydroxyl-C₁₋₃alkoxy includes hydroxymethoxy, 2-hydroxyethoxy, and3-hydroxypropoxy.

The C₁₋₆alkyl-carbonyl includes acetyl, ethylcarbonyl, propylcarbonyl,butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, and hexylcarbonyl.

The C₃₋₇cycloalkyl-carbonyl includes cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, andcycloheptylcarbonyl.

The C₁₋₆alkoxy-carbonyl includes methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl (i.e. C₁₋₃alkoxy-carbonyl),butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

The C₃₋₆cycloalkyloxy-carbonyl includes cyclopropyloxycarbonyl,cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, andcyclohexyloxycarbonyl.

The phenyl-C₁₋₆alkyl-carbonyl includes benzylcarbonyl, andphenethylcarbonyl.

The phenyl-C₁₋₆alkoxy-carbonyl includes benzyloxycarbonyl, andphenethyloxycarbonyl.

The C₁₋₆alkyl-carbamoyl includes methylcarbamoyl, ethylcarbamoyl,propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,sec-butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl andhexylcarbamoyl.

The C₁₋₆alkanoyl includes formyl, acetyl, propionyl, butyryl, andisobutryl.

The C₃₋₆alkenoyl includes vinylcarbonyl, 1-propenylcarbonyl,2-propenylcarbonyl, 1-butenylcarbonyl, and 1-pentenylcarbonyl.

The C₆₋₁₄aryl includes sphenyl, naphthyl, anthryl, phenanthryl, andacenaphthyl.

The cyanoC₆₋₁₄aryl includes 2-cyanophenyl, 3-cyanophenyl, and4-cyanophenyl.

The halogenoC₆₋₁₄aryl includes 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,6-difluorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, and2,6-dichlorophenyl.

The C₇₋₂₀aralkyl, that is, C₆₋₁₄aryl-C₁₋₆alkyl includes benzyl andphenethyl.

The C₆₋₁₄aryloxy includes phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

The mono- or di-C₁₋₆alkylamino includes methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, anddiethylamino.

The C₂₋₆alkenylamino includes vinylamino, allylamino, isopropenylamino,1-butenylamino, 2-butenylamino, 3-butenylamino, butadienylamino, and2-methylallylamino.

The C₁₋₆alkylamino-C₁₋₆alkyl includes methylaminomethyl,ethylaminomethyl, propylaminomethyl, methylaminoethyl, andethylaminoethyl.

The phenyl-C₁₋₆alkyl includes benzyl, and phenethyl.

Among the aforementioned substituents on a substituted hydrocarbongroup, (9) a 5- to 8-membered heterocyclic group containing 1 to 4heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, (11) C₆₋₁₄ aryl, (12) C₃₋₁₀cycloalkyl, (16) C₂₋₄alkynyl, (17)C₂₋₁₀ alkenyl and (18) C₇₋₂₀aralkyl may further have 1 to 4, preferably1 to 3 substituents at substitutable positions. The further substituentsmay be, for example, 1 to 3 groups, further preferably 1 or 2 groupsselected from (1) hydroxy, (2) amino, (3) mono- or di-C₁₋₄alkylamino(e.g. methylamino, ethylamino, propylamino, dimethylamino, diethylaminoetc.), (4) C₁₋₄alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.), (5) halogen (e.g.fluorine, chlorine, bromine, iodine), (6) nitro and (7) C₁₋₆alkyl (e.g.methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.).

When the hydrocarbon group is C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkenyl,C₆₋₁₄aryl or C₇₋₂₀aralkyl, it may be substituted with 1 to 3 C₁₋₆alkyl(e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.), and this C₁₋₆alkyl may be furthersubstituted with 1 to 3 hydroxyl, oxo, C₁₋₆alkoxy (e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, hexyloxy etc.), C₁₋₃ alkylthio (e.g. methylthio, ethylthio,propylthio, isopropylthio etc.), halogen (e.g. fluorine, chlorine,bromine, iodine), carbamoyl, etc.

The substituted C₁₋₆alkyl includes formyl (wherein methyl is substitutedwith oxo), carboxyl (wherein methyl is substituted with oxo andhydroxy), C₁₋₆alkoxycarbonyl (wherein methyl is substituted with oxo andalkoxy) (e.g. C₁₋₆alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl), hydroxyC₁₋₆alkyl (e.g.hydroxymethyl, hydroxyethyl, hydroxybutyl, hydroxypropyl etc.) andC₁₋₃alkoxy-C₁₋₆alkyl (e.g. methoxymethyl, ethoxymethyl, ethoxybutyl,propoxymethyl, propoxyhexyl etc.).

The number of the aforementioned substituents is 1 to 6, preferably 1 to5, particularly preferably 1 to 3, most preferably 1 or 2. The number ofsubstituents that the aforementioned substituents may further have ispreferably 1 to 4, particularly preferably 1 to 3, most preferably 1 or2.

For the group linking via a carbon atom, the acyl group of theoptionally substituted acyl group in the definition of R³⁸ and R³⁹includes a C₁₋₂₀acyl group such as formyl, C₁₋₆alkyl-carbonyl (e.g.acetyl, ethylcarbonyl, propylcarbonyl, tert-butylcarbonyl etc.),C₁₋₆alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl etc.), C₆1₄aryl-carbonyl (e.g. benzoyl, naphthoyletc.), C₆₋₁₄aryloxy-carbonyl (e.g. phenoxycarbonyl etc.),C₇₋₁₅aralkyl-carbonyl (e.g. C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl such asbenzylcarbonyl etc.), C₇₋₁₉ aralkyloxycarbonyl (e.g.C₆₋₁₄aryl-C₁₋₆alkoxy-carbonyl such as benzyloxycarbonyl etc.),C₂₋₄alkenyl-carbonyl (e.g. 2-propenylcarbonyl etc.),C₃₋₆cycloalkyl-carbonyl (e.g. cyclopropylcarbonyl etc.), tricyclicC₉₋₁₀bridging cyclic hydrocarbon-carbonyl (e.g. adamantylcarbonyl etc.),heterocycle-carbonyl (e.g. (1) 5-membered heterocycle-carbonylcontaining 1 to 4 heteroatoms selected from an oxygen atom, a sulfuratom and a nitrogen atom in addition to carbon atoms, such asthienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl, pyrrolinylcarbonyl,oxazolylcarbonyl, thiazolylcarbonyl, pyrazolylcarbonyl,imidazolylcarbonyl, imidazolinylcarbonyl, isoxazolylcarbonyl,isothiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl,1,3,4-oxadiazolylcarbonyl, furazanylcarbonyl,1,2,4-thiadiazolylcarbonyl, 1,2,3-thiadiazolylcarbonyl,1,2,5-thiadiazolylcarbonyl, 1,2,3-triazolylcarbonyl,1,2,4-triazolylcarbonyl, triazinylcarbonyl, triazolizinylcarbonyl, and1H- or 2H-tetrazolylcarbonyl; (2) 6-membered heterocycle-carbonylcontaining 1 to 4 heteroatoms selected from an oxygen atom, a sulfuratom and a nitrogen atom in addition to carbon atoms, such aspyridylcarbonyl, pyrimidinylcarbonyl, thiomorpholinylcarbonyl,morpholinylcarbonyl, triazinylcarbonyl, pyrrolidinylcarbonyl,piperidinylcarbonyl, pyranylcarbonyl, thiopyranylcarbonyl,1,4-oxazinylcarbonyl, 1,4-thiazinylcarbonyl, 1,3-thiazinylcarbonyl,piperazinylcarbonyl, triazinylcarbonyl, oxotriazinylcarbonyl,pyridazinylcarbonyl and pyrazinylcarbonyl, etc.), carbamoyl,N-C₁₋₆alkyl-carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl,propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl etc.), andN,N-di-C₁₋₆alkyl-carbamoyl (e.g. dimethylcarbamoyl, diethylcarbamoyl,dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl etc.).

The substituent of the optionally substituted acyl group includes thesame substituents as those of the aforementioned optionally substitutedhydrocarbon group.

In the Compound (II), the heterocyclic group of the heterocyclic groupor the optionally substituted heterocyclic group includes a 5- to8-membered heterocyclic group containing 1 to 4 heteroatoms selectedfrom an oxygen atom, a sulfur atom and a nitrogen atom in addition tocarbon atoms, a dicyclic or tricyclic fused heterocyclic group formed byfusing 2 or 3 of said heterocyclic groups which may be the same ordifferent, and a dicyclic or tricyclic fused heterocycle group formed byfusing said heterocyclic group with 1 or 2 benzene rings.

Embodiment of the heterocyclic group includes (1) a 5-memberedheterocyclic group containing 1 to 4 heteroatoms selected from an oxygenatom, a sulfur atom and a nitrogen atom in addition to carbon atoms,such as thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl,pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,4-thiadiazolyl,1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, triazinyl, triazolizinyl, and 1H- and 2H-tetrazolyl;(2) a 6-membered heterocyclic group containing 1 to 4 heteroatomsselected from an oxygen atom, a sulfur atom and a nitrogen atom inaddition to carbon atoms such as pyridyl, pyrimidinyl, thiomorpholinyl,morpholinyl, triazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl,1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl,oxotriazinyl, pyridazinyl and pyrazinyl; and (3) a dicyclic or tricyclicfused heterocyclic group containing 1 to 4 heteroatoms selected from anoxygen atom, a sulfur atom and a nitrogen atom in addition to carbonatoms, such as benzofuryl, benzothiazolyl, benzoxazolyl,tetrazolo[1,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl, benzimidazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, indolizinyl, indolyl, quinolizinyl, 1,8-naphthyridinyl,purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl,phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl andphenoxazinyl.

The substituent which the heterocyclic group may have includes (1)C₁₋₆alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.), (2) C₂₋₆alkenyl (e.g. vinyl,allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl,2-methylallyl, hexatrienyl etc.), (3) C₂₋₆alkynyl (e.g. ethynyl,2-propynyl, butynyl, 3-hexynyl etc.), (4) C₃₋₆ cycloalkyl (e.g.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), (5)C₅₋₇cycloalkenyl (e.g. cyclopentenyl, cyclohexenyl, cycloheptenyl etc.),(6) C₇₋₁₁laralkyl (e.g. C₆₋₁₀ aryl-C₁₋₅ alkyl such as benzyl andphenethyl, preferably benzyl), (7) C₆₋₁₄aryl (e.g. phenyl, naphthyl,anthryl, phenanthryl, acenaphthyl, anthracenyl etc., preferably phenyl),(8) C₁₋₆alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy etc.), (9)C₆₋₁₄aryloxy (e.g. phenoxy etc.), (10) C₁₋₆alkanoyl (e.g. formyl,acetyl, propionyl, butyryl, isobutyryl etc.), (11) C₆₋₁₄aryl-carbonyl(e.g. benzoyl etc.), (12) C₁₋₆alkanoyloxy (e.g. formyloxy, acetyloxy,propionyloxy, butyryloxy, isobutyryloxy etc.), (13)C₆₋₁₄aryl-carbonyloxy (e.g. benzoyloxy etc.), (14) carboxyl, (15)C₁₋₆alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl etc.), (16) carbamoyl, (17)N-mono-C₁₋₄alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl etc.), (18)N,N-di-C₁₋₄ alkylcarbamoyl (e.g. N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl etc.),(19) 3- to 6-membered cyclic aminocarbonyl (e.g. 1-aziridinylcarbonyl,1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl,N-methylpiperazinylcarbonyl, morpholinocarbonyl etc.), (20) halogen(e.g. fluorine, chlorine, bromine, iodine), (21) mono-, di- ortri-halogeno-C₁₋₄alkyl (e.g. chloromethyl, dichloromethyl,trifluoromethyl, trifluoroethyl etc.), (22) oxo, (23) amidino, (24)imino, (25) amino, (26) mono- or di-C₁₋₄ alkylamino (e.g. methylamino,ethylamino, propylamino, isopropylamino, butylamino, dimethylamino,diethylamino, dipropylamino, diisopropylamino, dibutylamino etc.), (27)a 3- to 6-membered cyclic amino group optionally containing 1 to 3heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogenatom in addition to carbon atoms and one nitrogen atom (e.g. aziridinyl,azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl,imidazolidinyl, piperidino, morpholino, dihydropyridyl,N-methylpiperazinyl, N-ethylpiperazinyl etc.), (28) C₁₋₆ alkanoylamino(e.g. formamido, acetamido, trifluoroacetamido, propionylamido,butyrylamido, isobutyrylamido etc.), (29) benzamido, (30)carbamoylamino, (31) N-C₁₋₄alkylcarbamoylamino (e.g.N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino,N-isopropylcarbamoylamino, N-butylcarbamoylamino etc.), (32)N,N-di-C₁₋₄alkylcarbamoylamino (e.g. N,N-dimethylcarbamoylamino, N,N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino,N,N-dibutylcarbamoylamino etc.), (33) C₁₋₃alkylenedioxy (e.g.methylenedioxy, ethylenedioxy etc.), (34) —B(OH)₂, (35) hydroxy, (36)epoxy(—O—), (37) nitro, (38) cyano, (39) mercapto, (40) sulfo, (41)sulfino, (42) phosphono, (43) sulfamoyl, (44) C₁₋₆alkylsulfamoyl (e.g.N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl,N-isopropylsulfamoyl, N-butylsulfamoyl etc.), (45) diC₁₋₆ alkylsulfamoyl(e.g. N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl etc.), (46) C₁₋₆alkylthio(e.g. methylthio, ethylthio, propylthio, isopropylthio, n-butylthio,sec-butylthio, tert-butylthio etc.), (47) phenylthio, (48) C₁₋₆alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl etc.), (49) phenylsulfinyl, (50) C₁₋₆alkylsulfonyl (e.g.methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl etc.) and(51) phenylsulfonyl.

The number of substituents which the heterocyclic group may have is 1 to6, preferably 1 to 3, further preferably 1 or 2.

The heterocyclic group of the optionally substituted heterocyclic grouplinking via a carbon atom includes a 5- to 8-membered heterocyclic groupcontaining 1 to 4 heteroatoms selected from an oxygen atom, a sulfuratom and a nitrogen atom in addition to carbon atoms, a dicyclic ortricyclic fused heterocyclic group formed by fusing 2 or 3 of saidheterocyclic groups which may be the same or different, and a dicyclicor tricyclic fused heterocyclic group formed by fusing said heterocyclicgroup with 1 or 2 benzene rings, wherein said heterocyclic group islinked via one of carbon atoms constituting the heterocycle.

Embodiment of the heterocyclic group linking via a carbon atom includes(1) a 5-membered heterocyclic group containing 1 to 4 heteroatomsselected from an oxygen atom, a sulfur atom and a nitrogen atom inaddition to carbon atoms, such as thienyl (e.g. 2- or 3-thienyl), furyl(e.g. 2- or 3-furyl), pyrrolyl (e.g. 2- or 3-pyrrolyl), oxazolyl (e.g.2-, 4- or 5-oxazolyl), thiazolyl (e.g. 2-, 4- or 5-thiazolyl), pyrazolyl(e.g. 3-, 4- or 5-pyrazolyl), pyrrolidinyl (e.g. 2- or 3-pyrrolidinyl),imidazolyl (e.g. 2-, 4- or 5-imidazolyl), imidazolinyl (e.g.2-imidazolinyl, 4-imidazolidinyl), isoxazolyl (e.g. 3-, 4- or5-isoxazolyl), isothiazolyl (e.g. 3-, 4- or 5-isothiazolyl), oxadiazolyl[e.g. 3- or 5-(1,2,4-oxadiazolyl), 2-, 5- or 6-(1,3,4-oxadiazolyl)],thiadiazolyl [e.g. 3- or 5-(1,2,4-thiadiazolyl), 2- or5-(1,3,4-thiadiazolyl), 4- or 5-(1,2,3-thiadiazolyl), 3- or4-(1,2,5-thiadiazolyl)], triazolyl [e.g. 2- or 5-(1,2,3-triazolyl), 3-or 5-(1,2,4-triazolyl)], and tetrazolyl [e.g. 5-(1H- or 2H-tetrazolyl)];(2) a 6-membered heterocyclic group containing 1 to 4 heteroatomsselected from an oxygen atom, a sulfur atom and a nitrogen atom inaddition to carbon atoms, such as pyridyl (e.g. 2-, 3- or 4-pyridyl),pyrimidinyl (e.g. 2-, 4- or 5-pyrimidinyl), thiomorpholinyl (e.g. 2- or3-thiomorpholinyl), morpholinyl (e.g. 2- or 3-morpholinyl), triazinyl(e.g. 3- or 6-triazinyl), piperidinyl (e.g. 2-, 3- or 4-piperidinyl),pyranyl (e.g. 2- or 3-pyranyl), thiopyranyl (e.g. 2- or 3-thiopyranyl),oxazinyl [e.g. 2- or 3-(1,4-oxazinyl)], thiazinyl [e.g. 2- or3-(1,4-thiazinyl), 1- or 4-(1,3-thiazinyl)], piperazinyl (e.g. 2- or3-piperazinyl), triazinyl (e.g. 3- or 6-triazinyl), pyridazinyl (e.g. 3-or 4-pyridazinyl), pyrazinyl (e.g. 2- or 3-pyrazinyl), and pyridazinyl(e.g. 3- or 4-pyridazinyl); and (3) a dicyclic or tricyclic fusedheterocyclic group containing 1 to 4 heteroatoms selected from an oxygenatom, a sulfur atom and a nitrogen atom in addition to carbon atoms,such as benzofuryl, benzothiazolyl, benzoxazolyl,tetrazolo[1,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl, benzimidazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, indolidinyl, indolyl, quinolizinyl, 1,8-naphthyridinyl,purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl,phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl andphenoxazinyl.

The substitutent which the heterocyclic group linking via a carbon atommay have includes the same substituents as those of the aforementionedoptionally substituted heterocyclic group.

The cyclic amino group of the aforementioned cyclic amino group or theaforementioned optionally substituted cyclic amino group includes a 5-to 7-membered nitrogen-containing cyclic group optionally further havingone atom selected from an oxygen atom, a sulfur atom and a nitrogenatom, for example, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, imidazolidinyl, imidazolinyl, imidazolyl,1,2,3-triazinyl, 1,2,3-triazolidinyl, 1,2,3-triazolyl,1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, azepinyl,hexamethyleneimino, oxazolidino, morpholino, thiazolidino andthiomorpholino. Inter alia, a 5- or 6-membered group is preferable. Forexample, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl,morpholino, or thiomorpholino is preferable.

The cyclic amino group may have 1 to 3 substituents at substitutablepositions, and the substituent includes (1) C₁₋₆alkyl (e.g. methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.), (2) C₆₋₁₄aryl (e.g. phenyl, naphthyl, anthryl,phenanthryl, acenaphthyl etc.), (3) C₇₋₁₀aralkyl (phenyl-C₁₋₄alkyl (e.g.benzyl, phenethyl etc.)), (4) benzhydryl, (5) C₁₋₆alkyl-carbonyl (e.g.acetyl, propionyl etc.), (6) C₆₋₁₄aryl-carbonyl (e.g. benzoyl etc.) and(7) C₁₋₆alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,hexyloxycabonyl etc.). A preferable example of the substituent isC₁₋₆alkyl. Inter alia, C₁₋₃alkyl is further preferable.

The homocyclic group of the optionally substituted homocyclic groupincludes an optionally fused 3- to 7-membered carbocyclic group such asa C₆₋₁₀aryl group (e.g. phenyl, naphthyl etc.), a C₃₋₇cycloalkyl group(e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyletc.), and C₃₋₇cycloalkenyl (e.g. cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl etc.).

The homocyclic group may have 1 to 6, preferably 1 to 3, furtherpreferably 1 or 2 substituents at substitutable positions. Thesubstituent includes (1) C₁₋₁₅alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl etc.) optionally substituted with 1 to 3, preferably 1 or 2halogen (e.g. fluorine, chlorine, bromine, iodine) (preferably,C₁₋₆alkyl optionally substituted with halogen), (2) C₃₋₁₀cycloalkyl(e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl etc.), (3) C₂₋₁₀alkenyl (e.g. vinyl,allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl,2-methylallyl, hexatrienyl, 3-octenyl etc.), (4) C₂₋₁₀alkynyl (e.g.ethynyl, 2-propynyl, butynyl, 3-hexynyl etc.), (5) c₃-₁₀cycloalkenyl(e.g. cyclopropenyl, cyclopentenyl, cyclohexenyl etc.), (6) C₆₋₁₀aryl(e.g. phenyl, naphthyl etc.), (7) C₇₋₂₀aralkyl (e.g. benzyl, phenethyletc.), (8) nitro, (9) hydroxyl, (10) mercapto, (11) oxo, (12) thioxo,(13) cyano, (14) carbamoyl, (15) carboxyl, (16) C₁₋₆alkoxy-carbonyl(e.g. methoxycarbonyl, ethoxycarbonyl etc.), (17) sulfo, (18) halogen(e.g. fluorine, chlorine, bromine, iodine), (19) C₁₋₆alkoxy (e.g.methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, hexyloxy etc.), (20) C₆₋₁₀aryloxy (e.g. phenoxyetc.), (21) C₁₋₆acyloxy (e.g. C₁₋₆ alkanoyloxy such as acetoxy,propionyloxy etc.), (22) C₁₋₆ alkylthio (e.g. methylthio, ethylthio,propylthio, isopropylthio, butylthio, tert-butylthio etc.), (23) C₆₋₁₀arylthio (e.g. phenylthio etc.), (24) C₁₋₆alkylsulfinyl (e.g.methylsulfinyl, ethylsulfinyl etc.), (25) C₆₋₁₀arylsulfinyl (e.g.phenylsulfinyl etc.), (26) C₁₋₆alkylsulfonyl (e.g. methylsulfonyl,ethylsulfonyl etc.), (27) C₆₋₁₀arylsulfonyl (e.g. phenylsulfonyl etc.),(28) amino, (29) C₁₋₆acylamino (e.g. C₁₋₆alkanoylamino such asacetylamino, propionylamino etc.), (30) mono- or di-C₁₋₄alkylamino (e.g.methylamino, ethylamino, propylamino, isopropylamino, butylamino,dimethylamino, diethylamino etc.), (31) C₃₋₈cycloalkylamino (e.g.cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylaminoetc.), (32) C₆₋₁₀arylamino (e.g. anilino etc.), (33) C₁₋₆alkanoyl (e.g.formyl, acetyl, hexanoyl etc.), (34) C₆₋₁₀aryl-carbonyl (e.g. benzoyletc.), and (35) a 5- or 6-membered heterocyclic group containing 1 to 4heteroatoms selected from oxygen, sulfur and nitrogen in addition tocarbon atoms [e.g. thienyl (e.g. 2- or 3-thienyl), furyl (e.g. 2- or3-furyl), pyrazolyl (e.g. 3-, 4- or 5-pyrazolyl), thiazolyl (e.g. 2-, 4-or 5-thiazolyl), isothiazolyl (e.g. 3-, 4- or 5-isothiazolyl), oxazolyl(e.g. 2-, 4- or 5-oxazolyl), isoxazolyl (e.g. 3-, 4- or 5-isoxazolyl),imidazolyl (e.g. 2-, 4- or 5-imidazolyl), triazolyl (e.g. 1,2,3- or1,2,4-triazolyl), tetrazolyl (e.g. 1H or 2H-tetrazolyl), pyridyl (e.g.2-, 3- or 4-pyridyl), pyrimidinyl (e.g. 2-, 4- or 5-pyrimidinyl),pyridazinyl (e.g. 3- or 4-pyridazinyl), quinolyl, isoquinolyl, indolyletc.].

The optionally substituted hydroxy represented by R³⁸ or R⁴⁰ includesthe aforementioned group represented by the formula —OR⁴³ wherein R⁴³ isas defined above.

In the aforementioned formula, R³¹, R³² and R³³ are the same ordifferent and preferably each is (i) hydrogen or (ii) the aforementionedgroup linking via a carbon atom, a nitrogen atom or an oxygen atom.Inter alia, preferably, R³¹ is an optionally substituted C₁₋₁₅alkyl,C₃₋₁₀cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkenyl,C₆₋₁₄aryl, C₇₋₂₀aralkyl or C₁₋₂₀acyl group, a nitro group, a grouprepresented by the formula —NR⁴⁰R⁴¹ wherein R⁴⁰ and R⁴¹ are as definedabove, or a group represented by the formula —OR⁴³ wherein R⁴³represents a hydrogen atom, or an optionally substitutedC₁₋₁₀hydrocarbon, C₁₋₂₀acyl, C₁₋₂₀ alkylsulfonyl, C₆₋₁₄arylsulfonyl or a5- to 8-membered heterocyclic group (same as the aforementioned “5- to8-membered heterocyclic group containing 1 to 4 heteroatoms selectedfrom an oxygen atom, a sulfur atom and a nitrogen atom in addition tocarbon atoms”), and at least one of R³² and R³³ is hydrogen and theother is the aforementioned group linking via a carbon atom, a nitrogenatom or an oxygen atom (preferably, both of R³² and R33 are hydrogen).

R³¹ is preferably a C₁₋₁₀alkyl group (preferably, C₁₋₆ alkyl group)optionally substituted with 1 to 3, preferably 1 hydroxy, a nitro group,an amino group, a group represented by the formula —NR⁴⁰R⁴¹ wherein R⁴⁰represents hydrogen, and R⁴¹ represents C₁₋₆alkyl-carbonyl optionallysubstituted with 1 to 3, preferably 1 hydroxy, C₁₋₆ alkylamino-carbonyloptionally substituted with 1 to 3, preferably 1 C₁₋₆alkoxy (e.g.methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, hexyloxy etc.), or C₆₋₁₄arylamino-carbonyl, or agroup represented by the formula —OR⁴³ wherein R⁴³ represents hydrogen,C₁₋₁₀alkyl optionally substituted with 1 to 3, preferably 1 hydroxy,C₃₋₁₀cycloalkyl, C₁₋₆alkyl-carbonyl optionally substituted with 1 to 3,preferably 1 hydroxy, C₁₋₆alkylsulfonyl, or C₆₋₁₀arylsulfonyl.

In the aforementioned formula, R³⁴ is preferably (1) an optionallysubstituted C₁₋₁₀hydrocarbon group, (2) an optionally substitutedC₁₋₂₀acyl group, (3) an optionally substituted heterocyclic grouplinking via a carbon atom, (4) an optionally esterified or amidatedcarboxyl group or (5) a cyano group. Inter alia, preferably, R³⁴ is anoptionally substituted C₁₋₁₅alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₀ alkenyl,C₂₋₁₀alkynyl, C₃₋₁₀cycloalkenyl, C₆₋₁₀aryl or C₇₋₂₀ aralkyl group.Further preferably, R³⁴ is an optionally substituted C₁₋₆alkyl group(e.g. an optionally substituted aminoalkyl group). A preferable exampleof R³⁴ is a group represented by the formula —(CH₂)_(u)—NR⁴⁰R⁴¹ whereinu represents an integer of 1 to 3, R⁴⁰ represents hydrogen, anoptionally substituted C₁₋₁₀hydrocarbon group, an optionally substitutedC₁₋₂₀acyl group, optionally substituted hydroxy (a group represented bythe aforementioned formula —OR⁴³), an optionally substitutedheterocyclic group, or a group represented by the formula —S(O)_(t)R⁴²(wherein t represents an integer of 0 to 2, and R⁴² represents ahydrogen atom or an optionally substituted C₁₋₁₀ hydrocarbon group), andR⁴¹ represents hydrogen or a C₁₋₁₀hydrocarbon group, or R⁴⁰ and R⁴¹ maybe taken together with the adjacent nitrogen atom to form an optionallysubstituted cyclic amino group. More preferably, R³⁴ is halogen, hydroxyoptionally substituted with a C₁₋₂₀acyl group, or a C₁₋₃alkyl groupoptionally substituted with an amino group optionally substituted withC₁₋₁₀alkyl and/or C₆₋₁₄ aryl-C₁₋₁₀alkyl. Particularly preferably R³⁴ isN—C₁₋₆ alkyl-N-benzylaminomethyl.

In the aforementioned formula, the halogen represented by R³⁵ includesfluorine, chlorine, bromine and iodine.

Preferable examples of R³⁵ are hydrogen, an optionally substitutedC₁₋₁₅alkyl group, an optionally substituted C₃₋₁₀ cycloalkyl group, anoptionally substituted C₂₋₁₀alkenyl group, an optionally substitutedC₂₋₁₀alkynyl, an optionally substituted C₃₋₁₀cycloalkenyl group, anoptionally substituted C₆₋₁₄aryl group, an optionally substituted C₇₋₂₀aralkyl group, an optionally substituted C₁₋₂₀acyl group, an optionallyesterified or amidated carboxyl group, and a group represented by theformula —OR⁴³ wherein R⁴³ represents a hydrogen atom, or an optionallysubstituted C₁₋₁₅alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₁₀ cycloalkenyl, C₆₋₁₄aryl, C₇₋₂₀aralkyl, C₁₋₂₀acyl, C₁₋₂₀alkylsulfonyl, C₆₋₁₄arylsulfonyl or heterocyclic group. Inter alia, R³⁵is preferably hydrogen, a C₁₋₁₅alkyl group optionally substituted with 1to 3, preferably 1 C₆₋₁₄aryl or C₁₋₆alkoxy, C₁₋₆alkoxy-carbonyloptionally substituted with 1 to 3, preferably 1 hydroxy,C₁₋₆alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl etc.), C₆₋₁₄aryl-carbonyl (e.g. benzoyl etc.),C₆₋₁₄aryloxy-carbonyl (e.g. phenoxycarbonyl etc.), C₇₋₁₅aralkyl-carbonyl(e.g. benzylcarbonyl etc.), C₇₋₁₉aralkyloxy-carbonyl (e.g.benzyloxycarbonyl etc.), N-C₁₋₁₀alkyl-N-(C₁₋₁₀alkoxy)amino-carbonyl(e.g. N-methyl-N-methoxyamino-carbonyl etc.), C₁₋₁₅ alkyloxy orC₁₋₂₀arylsulfonyl. Further preferably, R³⁵ is (1) a C₁₋₆alkoxy-carbonylgroup, (2) a C₆₋₁₄aryl group optionally substituted with halogen orC₁₋₆alkoxy, or (3) a phenyl-C₁₋₃alkyl group.

In the aforementioned formula, R³⁶ is preferably hydrogen, or anoptionally substituted C₁₋₁₅alkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₁₀cycloalkenyl, C₆₋₁₄ aryl or C₇₋₂₀aralkyl group. Interalia, R³⁶ is preferably hydrogen or a C₁₋₁₀alkyl group, and furtherpreferably hydrogen or a C₁₋₆alkyl group.

In the aforementioned formula, examples of R³⁷ include an optionallysubstituted homocyclic group and a heterocyclic group, preferably aC₆₋₁₄aryl group. Further preferable examples of R³⁷ include a phenylgroup optionally substituted with 1 to 3, preferably 1 to 2 halogen orC₁₋₆alkoxy. Particularly preferable is a phenyl group optionallysubstituted with 1 or 2 halogen.

In Compound (II), m is an integer of 0 to 3, preferably m is an integerof 0 to 2, further preferably m is 0 or 1.

In the aforementioned formula, u is an integer of 1 to 3, preferably, uis 1 or 2, more preferably, u is 1.

In Compound (II), one of W and Y represents a nitrogen atom and theother represents a carbon atom, both of them represent nitrogen atoms,or X represents a nitrogen atom or a carbon atom. Therefore, Compound(II) includes compounds represented by the formulas

wherein respective symbols are as defined above, (preferably compoundsrepresented by the formulas (IIa), (IIb), (IIc), (IId), (IIe) and(IIg)). Inter alia, preferred is Compound (II) in which X is a nitrogenatom, inter alia, compounds represented by the formulas (IIc) and (IIe),most preferably, a compound represented by the formula (IIe).

Among Compound (II), preferred is a compound represented by the generalformula:

wherein respective symbols are as defined above. Inter alia, furtherpreferred is a compound in which R³¹ is (1) an amino group optionallysubstituted with (i) carbamoyl optionally substituted with C₁₋₆alkyl orC₁₋₆alkoxy or (ii) C₁₋₆alkyl-carbonyl, or (2) a C₁₋₆alkoxy groupoptionally substituted with C₃₋₆cycloalkyl; R³⁴ is aN-C₁₋₆alkyl-N-benzylaminomethyl group; R³⁵ is (1) a C₁₋₆alkoxy-carbonylgroup, (2) a C₆₋₁₄aryl group optionally substituted with halogen orC₁₋₆alkoxy, or (3) a phenyl-C₁₋₃alkyl group; and R³⁶ is a hydrogen atom.

Preferred is also a compound in which R³¹ is (1) a nitro group, (2) anamino group optionally substituted with 1 or 2 substituents selectedfrom (i) C₁₋₆alkyl optionally substituted with hydroxy, (ii)C₁₋₆alkyl-carbonyl optionally substituted with hydroxy, halogen orthienyl, (iii) C₆₋₁₀ aryl-carbonyl optionally substituted C₁₋₆alkyl,C₁₋₆alkoxy or halogen, (iv) C₃₋₆cycloalkyl-carbonyl, (v)C₂₋₄alkenyl-carbonyl, (vi) C₁₋₆alkoxy-carbonyl, (vii)C₁₋₆alkylamino-carbonyl, (viii) C₁₋₆alkoxyamino-carbonyl, (ix)phenylaminocarbonyl, (x) isoxazolylcarbonyl, thienylcarbonyl,thiazolylcarbonyl, pyrazolylcarbonyl or furylcarbonyl, each optionallysubstituted with 1 or 2 substituents selected from C₁₋₆alkyl, nitro andC₁₋₆alkoxy, (xi) pyridylcarbonyl, (xii) C₁₋₆alkylsulfonyl, (xiii)thienylsulfonyl and (xiv) phenylsulfonyl optionally substituted withC₁₋₆alkyl, (3) a pyrrolyl group, or (4) a hydroxy group optionallysubstituted with C₁₋₆alkyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl orC₁₋₆alkyl-carbonyl; R³⁴ represents a C₁₋₆alkyl group optionallysubstituted with 1 or 2 substituents selected from (1) halogen, (2)hydroxy and (3) amino optionally substituted with 1 or 2 substituentsselected from C₁₋₆alkyl, phenyl-C₁₋₃alkyl and di-C₁₋₆ alkylamino-C₁₋₃alkyl; R³⁵ is (1) halogen, (2) a phenyl group optionally substitutedwith halogen or C₁₋₆alkyl or (3) a carbonyl group substituted with (i)C₁₋₆alkyl, (ii) amino substituted with C₁₋₆alkyl and C₁₋₆alkoxy or (iii)C₁₋₆alkoxy; and R³⁶ is a hydrogen atom or a C₁₋₃ alkyl group.

Embodiment of Compound (II) includes8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(ethylaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid ethyl ester,8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(methoxyaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester, and8-(2,6-difluorobenzyl)-5,8-dihydro-2-[4-(ethylaminocarbonylamino)phenyl]-3-(N-methyl-N-benzylaminomethyl)-5-oxoimidazo[1,2-a]pyrimidine-6-carboxylicacid isopropyl ester.

Examples of a salt of Compound (II) are the same as those of a salt ofthe Compound (I) mentioned above.

Compound (II) can be prepared by a known method such as a methoddescribed in WO99/33831 or JP-A 11-315079, or the similar method.

In addition, the non-peptidic compound having gonadotropin releasinghormone antagonistic activity includes quinoline derivatives describedin WO97/14682 or JP-A 9-169735, imidazopyrimidine derivatives,pyrrolopyrimidine derivatives and triazolopyrimidine derivativesdescribed in WO01/29044, imidazopyrimidine derivatives andpyrrolopyrimidine derivatives described in WO00/69859, compoundsdescribed in WO01/55119, compounds described in WO97/44037, compoundsdescribed in WO97/44041, compounds described in WO97/44321, compoundsdescribed in WO97/44339, a3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalene derivativedescribed in Bioorganic & Medicinal Chemistry Letters 12 (2002)3467-3470, a 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenederivative and5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamidedescribed in Bioorganic & Medicinal Chemistry Letters 12 (2002)3635-3639.

The toxicity of the non-peptidic compound having GnRH antagonisticactivity is low.

The non-peptidic compound having GnRH antagonistic activity can beformulated into a pharmaceutical composition in various dosage formsaccording to a known method, and then orally or parenterallyadministered to a mammal (e.g. human, monkey etc.) suffering from hotflash.

In addition, the non-peptidic compound having GnRH antagonistic activitycan be used for suppressing occurrence of a feminized breast.

For administration, specifically, the non-peptidic compound having GnRHantagonistic activity is mixed with a pharmaceutically acceptablecarrier and then usually formulated into a solid preparation such as atablet, a capsule, a granule or a powder to be administered orally, oran injection, a suppository or a sublingual tablet to be administeredparenterally (e.g. intravenously, subcutaneously, or intramuscularly).Alternatively, the non-peptidic compound may be formulated into asustained-release preparation such as a sublingual tablet or amicrocapsule and then administered sublingually, subcutaneously orintramuscularly.

The pharmaceutically acceptable carrier includes various organic orinorganic carrier substances which are conventionally used aspharmaceutical material, and it is incorporated in a solid preparationas an excipient, a lubricant, a binder or a disintegrant; or in a liquidpreparation as a solvent, a solubilizer, a suspending agent, anisotonizing agent, a buffer or a soothing agent. If necessary,pharmaceutical additives such as preservatives, antioxidants, coloringagents and sweeteners can be used.

Preferable examples of the excipient include lactose, white sugar,D-mannitol, starch, crystalline cellulose and light silicic anhydride.Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc and colloidal silica. Preferable examples of the binderinclude crystalline cellulose, white sugar, D-mannitol, dextrin,hydroxypropylcellulose, hydroxypropylmethylcellulose andpolyvinylpyrrolidone. Preferable examples of the disintegrant includestarch, carboxymethylcellulose, carboxymethylcellulose calcium,croscarmellose sodium and carboxymethylstarch sodium. Preferableexamples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil and corn oil. Preferable examples of thesolubilizer include polyethylene glycol, propylene glycol, D-mannitol,benzyl benzoate, ethanol, trisaminomethane, cholesterol,triethanolamine, sodium carbonate and sodium citrate. Preferableexamples of the suspending agent include surfactants such asstearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride and monostearicacid glycerin; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose andhydroxypropylcelluloce. Preferable examples of the isotonizing agentinclude sodium chloride, glycerin and D-mannitol. Preferable examples ofthe buffer include phosphate buffer, acetate buffer, carbonate bufferand citrate buffer. Preferable examples of the soothing agent includebenzyl alcohol. Preferable examples of the preservative includeparahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethylalcohol, dehydroacetic acid and sorbic acid. Preferable examples of theantioxidant include sulfite and ascorbic acid.

A daily dose varies depending on severity of a symptom; the age, sex andweight of a subject to be administered; a time and an interval ofadministration, the nature, composition and kind of a pharmaceuticalpreparation; the kind of an active ingredient, being not limitedparticularly. For example, when orally administered for treating hotflash, a daily dose is usually 0.1 to 300 mg, preferably about 1 to 300mg, further preferably about 10 to 200 mg for an adult and is usuallyadministered in 1 to 4 divided doses.

The content of the non-peptidic compound having GnRH antagonisticactivity in the agent of the present invention is about 0.01 to 100% byweight of the total agent.

The non-peptidic compound having GnRH antagonistic activity may be usedin combination with a drug for lowering the level of a sex hormone [e.g.GnRH agonist, sex hormone synthesis inhibitor (e.g. aromatase inhibitorsuch as anastrozole and letrozole)], a sex hormone activity inhibitor(e.g. estrogen receptor antagonist such as tamoxifen, androgen receptorantagonist such as bicalutamide), a sex hormone preparation (estrogenpreparation such as premarin and raloxifene, corpus luteum hormone suchas medroxyprogesterone acetate, androgen preparation such as enanthicacid testosterone, and a combinatorial agent thereof), an osteoporosistreating agent (e.g. bisphosphonic acid drug), a central drug [e.g.antianxiety, sleep-introducing agent, schizophrenia treating agent,Parkinson's treating agent, anti-dementia agent (e.g. cerebralcirculation improving agent, cerebral metabolism activator etc.) etc.],a depressor, a diabetes treating agent, an anti-hyperlipemia agent, anutrient (e.g. vitamin agent), an analgesic, a digestion absorptionpromoter, a gastrointestinal drug, or the like.

The non-peptidic compound having GnRH antagonistic agent may be alsoused in combination with an acetylcholine esterase inhibitor (e.g.tacrine, donepezil, rivastigmine, galantamine, physostigmine-DDS,ipidacrine etc.), a muscarinic acetylcholine receptor agonist, nicotinicacetylcholine receptor agonist, a Ca antagonist (e.g. nimodipine etc.),a COX-2 inhibitor (e.g. rofecoxib, celecoxib etc.), an AMPA receptoragonist, a monoamine oxidase inhibitor (e.g. selegiline-DDS), amyloid βprotein secretion/aggregation inhibitor, or an Alzheimer type dementiatreating drug such as nifiracetam or Memantine.

An administration method of the non-peptidic compound having GnRHantagonistic activity and a concomitant drug are not particularlylimited as long as they are administered in combination. Suchadministration method includes (1) administration of a singlepreparation obtained by formulating the non-peptidic compound havingGnRH antagonistic activity and a concomitant drug into a preparation,(2) simultaneous administration of two preparations obtained byformulating the non-peptidic compound having GnRH antagonistic activityand a concomitant drug into separate preparations via the sameadministration route, (3) administration of two preparations obtained byformulating the non-peptidic compound having GnRH antagonistic activityand a concomitant drug into separate preparations via the sameadministration route at different times, (4) simultaneous administrationof two preparations obtained by formulating the non-peptidic compoundhaving GnRH antagonistic activity and a concomitant drug into separatepreparations via different administration routes, and (5) administrationof two preparations obtained by formulating the non-peptidic compoundhaving GnRH antagonistic activity and a concomitant drug into separatepreparations via different administration routes at different times(e.g. administration in an order of non-peptidic compound having GnRHantagonistic activity and then a concomitant drug, or vice verse).

The following Reference Examples and Examples further illustrate thepresent invention, but do not limit the present invention.

¹H-NMR spectrum was measured with a Varian GEMINI 200 (200 MHz) typespectrometer, JEOL. Ltd. LAMBDA300 (300 MHz) type spectrometer or BruccaAM 500 (500 MHz) type spectrometer using tetramethylsilane as aninternal standard, and a total δ value is indicated in ppm. Unlessotherwise indicated, “%” denotes weight percentage. A yield is denotedin mol/mol %. Other symbols used herein mean as follows:

s: singlet

d: doublet

t: triplet

dt: double triplet

m: multiplet

br: broad

Room temperature indicates, but not limited to, the range of about 15 to25° C. Lactose, corn starch and magnesium stearate used in Examples wereproducts meeting the specification of the Japanese Pharmacopoeia 14thEdition.

EXAMPLES REFERENCE EXAMPLE 12-Amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethylester

A mixture of 4-nitrophenylacetone (35.0 g, 195 mmol), ethyl cyanoacetate(23.8 g, 195 mmol), ammonium acetate (3.1 g, 40 mmol) and acetic acid(9.1 ml, 159 mmol) was heated to reflux for 24 hours in a Dean Starkapparatus with removing produced water. After cooling, the reactionsolution was concentrated under reduced pressure and the residue waspartitioned between dichloromethane and aqueous sodium bicarbonate. Theorganic layer was washed with an aqueous sodium chloride solution, dried(MgSO₄), and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography. The resultingoil was dissolved in ethanol, sulfur (5.0 g, 160 mmol) and diethylamine(16.0 ml, 160 mmol) were added, and the mixture was stirred at 60 to 70°C. for 2 hours. After cooling, the reaction solution was concentratedunder reduced pressure, and the residue was partitioned betweendichloromethane and aqueous sodium bicarbonate. The organic layer waswashed with an aqueous sodium chloride solution, dried (MgSO₄), and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography and then crystallized fromether-hexane to obtain the title compound (22.2 g, 52%) as a red platecrystal.

MP: 168-170° C. (recrystallization from ether-hexane) ElementaryAnalysis for C₁₄H₁₄N₂O₄S C (%) H (%) N (%) Calculated: 54.89; 4.61; 9.14Found: 54.83; 4.90; 9.09

¹H-NMR (200 MHz, CDCl₃) δ: 1.39 (3H, t, J=7.1 Hz), 2.40 (3H, s), 4.34(2H, q, J=7.1 Hz), 6.27 (2H, br), 7.48 (2H, d, J=8.7 Hz), 8.23 (2H, d,J=8.7 Hz). IR (KBr): 3446, 3324, 1667, 1580, 1545, 1506, 1491, 1475,1410, 1332 cm⁻¹.

REFERENCE EXAMPLE 25-Methyl-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Phenyl isocyanate (2.66 ml, 24.48 mmol) was added to a solution of thecompound of Reference Example 1 (5.00 g, 16.32 mmol) in pyridine (30 ml)and the mixture was stirred at 45° C. for 6 hours. The reaction solutionwas concentrated under reduced pressure and the resulting residue wasdissolved in ethanol (6 ml). To this solution was added 28% sodiummethoxide (7.86 g, 40.80 mmol), and the reaction solution was stirred atroom temperature for 2 hours. Thereto 2N hydrochloric acid (25 ml, 50mmol) was added and the ethanol solvent was distilled off under reducedpressure. The resulting residue was filtered, washed with water-ethanol,dried under reduced pressure, and then recrystallized from ethanol toobtain the title compound (6.09 g, 98%) as a yellow powder.

mp: >300° C.

Elementary Analysis for C₁₉H₁₃N₃O₄S.0.3H₂O C (%) H (%) N (%) Calculated:59.30; 3.56; 10.92 Found: 59.56; 3.52; 10.93

¹H-NMR (30OMHz, DMSO-d₆) δ: 2.50 (3H, s), 7.31-7.46 (5H, m), 7.78 (2H,d, J=8.8 Hz), 8.32 (2H, d, J=8.8 Hz), 12.50 (1H, s). IR (KBr): 1715,1657, 1593, 1510 cm⁻¹.

REFERENCE EXAMPLE 31-(2,6-Difluorobenzyl)-5-methyl-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of the compound of Reference Example 2 (52.54 g, 0.131mol) in dimethylformamide (1.0 L) were added potassium carbonate (19.00g, 0.138 mol), potassium iodide (22.90 g, 0.138 mol) and2,6-difluorobenzyl chloride (22.40 g, 0.138 mol), and the mixture wasstirred at room temperature for 2 hours. The reaction solution wasconcentrated and the residue was partitioned between chloroform and anaqueous sodium chloride solution. The aqueous layer was extracted withchloroform. The extracts were combined, washed with an aqueous sodiumchloride solution and then dried (MgSO₄). The solvent was distilled offunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (61.50 g, 93%) as apale yellow crystal.

mp: 280-282° C.

Elementary Analysis for C₂₆H₁₇N₃O₄SF₂ C (%) H (%) N (%) Calculated:61.78; 3.39; 8.31 Found: 61.67; 3.46; 8.21

¹H-NMR (300 MHz, CDCl₃) δ: 2.57 (3H, s), 5.38 (2H, s), 6.94 (2H, d,J=8.1 Hz), 7.42-7.58 (8H, m), 8.29 (2H, d, J=8.8 Hz). IR (KBr): 1719,1669, 1524, 1473 cm⁻¹.

REFERENCE EXAMPLE 45-Bromomethyl-1-(2,6-difluorobenzyl)-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

A mixture of the compound of Reference Example 3 (30.34 g, 0.060 mol),N-bromosuccinimide (12.81 g, 0.072 mol), α, α′-azobisisobutyronitrile(1.15 g, 0.007 mol) and chlorobenzene (450 ml) was stirred at 85° C. for3 hours. After cooling, the reaction solution was washed with an aqueoussodium chloride solution and dried (MgSO₄). The solvent was thendistilled off under reduced pressure. The residue was recrystallizedfrom ethyl acetate to obtain the title compound (80.21 g, 100%) as ayellow needle crystal.

mp: 228-229° C.

¹H-NMR (300 MHz, CDCl₃) δ: 4.77 (2H, s), 5.38 (2H, s), 6.96 (2H, t,J=8.1 Hz), 7.29-7.58 (6H, m), 7.79 (2H, d, J=8.5 Hz), 8.35 (2H, d, J=8.5Hz). IR (KBr): 1721, 1680, 1524, 1473, 1348 cm⁻¹. FAB-Mass m/z 584 (MH)⁺

REFERENCE EXAMPLE 55-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of the compound of Reference Example 4 (80.00 g, 0.119mol) in dimethylformamide (600 ml) were added ethyldiisopropylamine(27.00 ml, 0.155 mol) and benzylmethylamine (18.45 ml, 0.143 mol) underice-cooling. After stirred at room temperature for 2 hours, the reactionsolution was concentrated and the resulting residue was partitionedbetween ethyl acetate and aqueous saturated sodium bicarbonate. Theaqueous layer was extracted with ethyl acetate and the organic layerswere combined and then dried (MgSO₄). The solvent was then distilled offunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain a yellow oil (74.90 g, 100%), which wasrecrystallized from ethyl acetate to obtain the title compound as ayellow needle crystal.

mp: 173-174° C. Elementary Analysis for C₃₄H₂₆N₄O₄SF₂.0.5H₂O C (%) H (%)N (%) Calculated: 64.45; 4.29; 8.84 Found: 64.50; 4.24; 8.82

¹H-NMR (300 MHz, CDCl₃) [free amine] δ: 1.31 (3H, s), 3.60 (2H, s), 3.96(2H, s), 5.39 (2H,s), 6.95 (2H, t, J=8.2 Hz), 7.18-7.55 (11H, m), 8.02(2H, d, J=9.0 Hz), 8.26 (2H, d, J=9.0 Hz). IR (KBr) [hydrochloride]:1719, 1678, 1597, 1520 cm⁻¹.

REFERENCE EXAMPLE 66-(4-Aminophenyl)-5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of the compound of Reference Example 5 (3.00 g, 4.80 mmol)in formic acid (30 ml) were added 1M hydrogen chloride-ether (14.4 ml,14.4 mmol) and 10% palladium carbon powder (300 mg) under ice-cooling,and the mixture was stirred at the normal temperature and the normalpressure over 2 hours, followed by hydrogenation. The reaction solutionwas filtered with Celite and the filtrate was concentrated under reducedpressure. The resulting residue was partitioned between dichloromethaneand aqueous saturated sodium bicarbonate. The aqueous layer wasextracted with dichloromethane and the organic layers were combined andthen dried (MgSO₄). The solvent was then distilled off under reducedpressure. The resulting residue was purified by silica gel columnchromatography to obtain the title compound (2.41 g, 84%) as a whitecrystal.

mp: 205-207° C. Elementary Analysis for C₃₄H₂₈N₄O₂SF₂.0.1AcOEt. 1.2H₂OC(%) H(%) N(%) Calculated: 66.09; 5.03; 8.96 Found: 66.93; 4.94; 8.67¹H-NMR (300 MHz, CDC1₃) 6: 2.05 (3H, s), 3.56 (2H, s), 3.83 (2H, br),3.88 (2H, s), 5.36 (2H, s), 6.70 (2H, d, J=8.8 Hz), 6.88-6.94 (2H, m),7.21-7.31 (8H, m), 7.41-7.53 (5H, m). IR (KBr): 1715, 1657, 1628, 1537cm⁻¹.

REFERENCE EXAMPLE 75-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

To a solution of the compound of Reference Example 6 (5.0 g, 8.41 mmol)in dichloromethane (120 ml) was added triethylamine (2.34 ml, 16.82mmol) under ice-cooling and the mixture was stirred. To this reactionsolution was added N,N′-carbonyldiimidazole (2.73 g, 16.82 mmol) underice-cooling. The mixture was stirred at room temperature for 42 hours.Then under ice-cooling, O-methylhydroxylamine hydrochloride (7.02 g,84.08 mmol) and triethylamine (11.7 ml, 84.08 mmol) were added. Thereaction solution was stirred for 3 hours at room temperature. Thereaction solution was partitioned between chloroform and aqueoussaturated sodium bicarbonate. The aqueous layer was extracted withchloroform and the extracts were combined, washed with an aqueous sodiumchloride solution and then dried (MgSO₄). The solvent was distilled offunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the pale yellow solid, which wasrecrystallized from chloroform-ether to obtain the title compound as awhite crystal (4.52 g, 80%).

mp: 204-205° C. Elementary Analysis for C₃₆H₃₁N₅O₄SF₂ C (%) H (%) N (%)Calculated: 64.75; 4.68; 10.49 Found: 64.61; 4.67; 10.31

¹H-NMR (300 MHz, CDCl₃) δ: 2.05 (3H, s), 3.57 (2H, s), 3.82 (3H, s),3.90 (2H, s), 5.37 (2H, s), 6.92 (2H, d, J=8.2 Hz), 7.16-7.31 (9H, m),7.42-7.57 (5H, m), 7.63 (1H, s), 7.73 (2H, d, J=8.8 Hz). IR (KBr): 3338,3064, 1717, 1669, 1628, 1591, 1531, 1470 cm⁻¹.

REFERENCE EXAMPLE 85-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

To a solution of the white crystal of Reference Example 7 (38.34 g,57.42 mmol) in dichloromethane (800 ml) was added 1M etheric hydrogenchloride (100 ml) under ice-cooling, and the mixture was stirred at thesame temperature for 10 minutes. The reaction solution was concentratedunder reduced pressure, and the resulting residue was recrystallizedfrom methanol-ether to obtain the title compound (40.0 g, 99%) of awhite powdery crystal. mp: 182-185° C. Elementary Analysis forC₃₆H₃₁N₅O₄SF₂.HCl .0.5H₂O C (%) H (%) N (%) Calculated: 60.63; 4.66;9.82 Found: 60.45; 4.68; 9.62

IR (KBr): 3440, 3042, 1713, 1665, 1628, 1593, 1539, 1473 cm⁻¹. FAB-Massm/z 668 (MH)⁺

EXAMPLE 1

Using the compound of Reference Example 7 (100 mg), lactose (165 mg),corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1mg), a tablet is produced according to a conventional method.

EXPERIMENTAL EXAMPLE 1

(1) Preparation of ¹²⁵I-leuprorelin

Then microliters of a 3×10⁻⁴ M aqueous leuprorelin solution and 10 μl of0.01 mg/ml lactoperoxidase were put into a tube and thereto 10 μl (37MBq) of a Na¹²⁵I solution was added. The mixture was stirred, and 10 μlof 0.001% H₂O₂ was added, followed by reaction at room temperature for20 minutes. The reaction was stopped by addition of 700 μl of a 0.05%TFA solution and the reaction mixture was purified by reverse phaseHPLC. Conditions of HPLC are shown below. ¹²⁵I-leuprorelin was eluted ata retention time of 26 to 27 minutes.

Column: TSKgel ODS-80™ (TM indicates registered trademark; the samehereinafter)

CTR (4.6 mm×10 cm) eluent:

Solvent A (0.05% TFA)

Solvent B (40% CH₃CN-0.05% TFA)

0 minutes (100% Solvent A)—3 minutes (100% Solvent A)—7 minutes (50%Solvent A+50% Solvent B)—40 minutes (100% Solvent B)

Elution temperature: room temperature

Elution rate: 1 ml/min

(2) Preparation of Anterior Pituitary Membrane Fraction Containing RatGnRH Receptor

Anterior pituitaries were removed from 40 Whister rats (8 weeks old,male) and washed with an ice-cooled homogenate buffer ({25 mM Tris[tris(hydroxymethyl)aminomethane]-HCl}, 0.3M saccharose, 1 mm EGTA(glycol ether diaminetetraacetic acid), 0.25 mM PMSF(phenylmethylsulfonyl fluoride), 10 U/ml aprotinin, 1 μg/ml pepstatin,20 μg/ml leupeptin, 100 μg/ml fosforamidon, 0.03% sodium azide, pH 7.6).The pituitary glands were floated on 2 ml of a homogenate buffer andhomogenized using a Polytron. homogenizer. After centrifugation at 700×gfor 15 minutes, the supernatant was put in a supercentrifuge tube andcentrifuged at 100,000×g for 1 hour to obtain precipitates of a membranefraction. To the precipitates was added 2 ml of an assay buffer (25 mMTris-HCl, 1 mm EDTA (ethylenediaminetetraacetic acid) (0.1% BSA (bovineserum albumin), 0.25 mM PMSF, 1 μg/ml pepstatin, 20 μg/ml leupeptin, 100μg/ml fosforamidon, 0.03% sodium azide, pH 7.5) to suspend theprecipitates therein, which was centrifuged at 100,000×g for 1 hour. Amembrane fraction was collected as precipitates, suspended again in 10ml of the assay buffer, dispensed, and then stored at −80° C., which wasthawed before use.

(3) Preparation of CHO (Chinese Hamster Ovary) Cell Membrane FractionContaining Human GnRH Receptor

Human GnRH receptor-expressing CHO cells (10⁹ cells) were suspended in aphosphate-buffered physiological saline (PBS-EDTA) containing 5 mM EDTAand then centrifuged at 100×g for 5 minutes. To the pellet of cells wasadded 10 ml of a cell homogenate buffer (10 mm NaHCO₃, 5 mM EDTA, pH7.5), and this was homogenized using a Polytron homogenizer. Aftercentrifugation at 400×g for 15 minutes, the supernatant was put in asupercentrifuge tube and centrifuged at 100,000×g for an hour to obtainprecipitates of a membrane fraction. The precipitates were suspended in2 ml of the assay buffer and centrifuged at 100,000×g for an hour. Amembrane fraction was collected as precipitates, suspended again in 20ml of the assay buffer, dispensed, and stored at −80° C., which wasthawed before use.

(4) Measurement of ¹²⁵I-leuprorelin Binding Inhibiting Rate

The rat and human membrane fractions prepared in the above (2) and (3)were diluted with the assay buffer to 200 μg/ml each, 188 μl of whichwas put into each tube. When the anterior pituitary membrane fractionwas used, 2 μl of a 0.1 mM solution of a compound in 60% DMSO (dimethylsulfoxide) and 10 μl of 38 nM ¹²⁵I-leuprorelin were added at the sametime. When the human GnRH receptor-expressing CHO cell membrane fractionwas used, 2 μl of a 2 mM solution of a compound in 60% DMSO and 10 μl of38 nM ¹²⁵I-leuprorelin were added at the same time. In order to measurea maximum binding amount, a reaction solution to which 2 μl of 60% DMSOand 10 μl of 38 nM ¹²⁵I-leuprorelin had been added was prepared. Inaddition, in order to measure a non-specific binding amount, a reactionsolution to which 2 μl of 100 μM leuprorelin solution in 60% DMSO and 10μl of 38 nM 125I-leuprorelin had been added was prepared.

When the anterior pituitary membrane fraction was used, a reaction wasperformed at 4° C. for 90 minutes and, when the human GnRHreceptor-expressing CHO cell membrane fraction was used, a reaction wasperformed at 25° C. for 60 minutes. After the reaction, the reactionsolution was suction-filtered using a polyethyleneimine-treated Whatmannglass filter (GF-F). After the filtration, radioactivity of¹²⁵I-leuprorelin remaining on the filer was measured using a γ-counter.(TB-SB)/(TB-NSB)×100 (SB: radioactivity when compound is added, TB:maximum binding radioactivity, NSB: non-specific binding radioactivity)was calculated to obtain a binding inhibiting rate (%) of each testsubstance. In addition, by varying the concentration of a testsubstance, an inhibiting rate was obtained, and the concentration of atest substance which inhibits the binding by 50% (IC₅₀ value) wascalculated from the Hill plot. Results are shown below: TABLE 1 Bindinginhibiting rate (%) IC₅₀ value Test substance Rat (1 μM) (μM) HumanCompound of 27 0.0001 Reference Example 8

EXPERIMENTAL EXAMPLE 2

To 32 premenopausal healthy females (20 years old to 45 years old), 1 to25 mg/day of the compound of Reference Example 7 was administered for 14days. As a result, the serum estradiol concentration was reduced, buthot flash was not observed.

INDUSTRIAL APPLICABILITY

A preventing or treating agent for hot flash which comprises anon-peptidic compound having gonadotropin releasing hormone antagonisticactivity of the present invention is low toxic and has excellent hotflash preventing or treating effect.

1. A preventing or treating agent for hot flash which comprises anon-peptidic compound having gonadotropin releasing hormone antagonisticactivity.
 2. The agent according to claim 1, wherein the compound is acompound capable of entering the brain.
 3. The agent according to claim1, wherein the compound is a fused heterocyclic compound.
 4. The agentaccording to claim 1, wherein the compound is a compound represented bythe formula:

wherein R¹ represents (1) a hydrogen atom, (2) a group linking via acarbon atom, (3) a group linking via a nitrogen atom, (4) a grouplinking via an oxygen atom or (5) a group linking via a sulfur atom, R²represents (1) a hydrogen atom, (2) a group linking via a carbon atom,(3) a group linking via a nitrogen atom, (4) a group linking via anoxygen atom or (5) a group linking via a sulfur atom, R³ represents (1)a hydrogen atom, (2) alkyl or (3) —(CH₂)_(p)Q (wherein p represents aninteger of 0 to 3 and Q represents an optionally substituted homocyclicgroup or an optionally substituted heterocyclic group),

R⁴ represents (1) a hydrogen atom, (2) alkyl optionally substituted withalkoxy, (3) optionally substituted aryl, (4) optionally substitutedaralkyl or (5) optionally substituted cycloalkyl, R⁵ represents (1) ahydrogen atom, (2) formyl, (3) cyano, (4) C₁₋₆alkyl optionallysubstituted with (i) a group linking via a sulfur atom or (ii) a grouplinking via an oxygen atom, (5) an optionally substituted heterocyclicgroup, (6) a group linking via a nitrogen atom, (7) a group linking viaan oxygen atom, (8) a group linking via a sulfur atom, (9) optionallyesterified, thioesterified or amidated carboxyl or (10) —C(O)R⁷ (whereinR⁷ represents an optionally substituted hydrocarbon group), and R⁶represents (1) a hydrogen atom or (2) a group linking via a carbon atom,or a salt or prodrug thereof.
 5. The agent according to claim 4, whereinR¹ is optionally substituted C₆₋₁₄ aryl, R² is (1) C₁₋₃alkyl substitutedwith a group linking via a nitrogen atom or (2) a group linking via anitrogen atom, R³ is —(CH₂)_(p)Q (wherein p represents an integer of 0to 3 and Q represents an optionally substituted homocyclic group or anoptionally substituted heterocyclic group),

R⁴ is (1) C₁₋₆alkyl optionally substituted with C₁₋₆alkoxy or (2)optionally substituted C₆₋₁₄aryl.
 6. The agent according to claim 1,wherein the compound is a compound represented by the formula:

wherein R²¹ and R²² each represent (1) a hydrogen atom (2) hydroxy (3)C₁₋₄alkoxy, (4) C₁₋₄alkoxy-carbonyl or (5) optionally substitutedC₁₋₄alkyl, R²³ represents (1) a hydrogen atom, (2) halogen, (3) hydroxyor (4) optionally substituted C₁₋₄alkoxy, or two R²³ adjacent to eachother may be linked to form C₁₋₄ alkylenedioxy, R²⁴ represents (1) ahydrogen atom or (2) C₁₋₄alkyl, and R²⁶ represents (1) optionallysubstituted C₁₋₄alkyl or (2) a group represented by the formula:

wherein R²⁵ represents a hydrogen atom or may be taken together with R²⁴to form a heterocycle, and n represents an integer of 0 to 5, or a saltthereof.
 7. A method for preventing or treating hot flash, whichcomprises administering an effective amount of a non-peptidic compoundhaving gonadotropin releasing hormone antagonistic activity to a mammal.8. Use of a non-peptidic compound having gonadotropin releasing hormoneantagonistic activity for preparation of a preventing or treating agentfor hot flash.